Abiraterone prodrugs

ABSTRACT

Sustained-release abiraterone prodrug formulations, methods, and kits for parenteral administration to a subject having a sex hormone-dependent benign or malignant disorder such as prostate cancer, a syndrome due to androgen excess, and/or a syndrome due to glucocorticoid excess such as hypercortisolemia.

This application claims the benefit of U.S. Provisional Application Nos.62/814,568, filed Mar. 6, 2019, and 62/849,259, filed May 17, 2019, thecontent of each of which is incorporated herein by reference in itsentirety.

The present disclosure relates generally to novel prodrugs ofabiraterone and long-acting, depot-based parenteral formulations ofabiraterone prodrugs. The disclosure is subject to a wide range ofapplications, such as for intramuscular (IM) injection to a patientsuffering from an androgen or estrogen hormone-dependent benign ormalignant disorder, including various cancers (such as prostate cancer,bladder cancer, hepatocellular carcinoma, lung cancer, breast cancer,and ovarian cancer, etc.), and for the treatment of non-oncologicsyndromes due to the overproduction of androgens (including bothclassical and nonclassical congenital adrenal hyperplasia,endometriosis, polycystic ovary syndrome precocious puberty, hirsutism,etc.) or due to the overproduction of glucocorticoids, typicallycortisol in conditions such as Cushing's syndrome or Cushing's disease.

BACKGROUND

Abiraterone ((3β)-17-(pyridin-3-yl) androsta-5, 16-dien-3-ol; CAS #:154229-19-3); Formula: C₂₄H₃₁NO; Mol. Weight: 349.5 g/mol) is aninhibitor of CYP17A1 (which is a member of the cytochrome P450superfamily of enzymes that catalyze the synthesis of cholesterol,steroids and other lipids and are involved in drug metabolism). CYP17A1has both 17α-hydroxylase activity and 17,20-lyase activity. Abirateronepotently and selectively inhibits both CYP17A1 17α-hydroxylase and17,20-lyase enzyme activities. The 17α-hydroxylase activity of CYP17A1is required for the generation of glucocorticoids such as cortisol.However, both the hydroxylase and 17,20-lyase activities of CYP17A1 arerequired for the production of androgenic (e.g., androstenedione,testosterone, and dihydrotestosterone) and estrogenic (estrone,estradiol. estratriol) steroids through the conversion of17α-hydroxypregnenolone to the sex steroid precursor,dehydroepiandrosterone, see FIG. 14D. Thus, abiraterone interferes withthe synthesis of androgens and estrogens in the gonads (primarily in thetestes and overies) and extra-gonadally (e.g., in the adrenals and inthe tumors themselves).

Though abiraterone itself is poorly absorbed, it can be administeredorally as an abiraterone acetate prodrug. Abiraterone acetate is alsopoorly absorbed, but can be converted to abiraterone in the gut, whichis poorly absorbed into the bloodstream following the cleavage of theacetate prodrug. Abiraterone acetate ((3β)-17-(3-Pyridyl)androsta-5,acetate; CAS #154229-18-2) is approved in the United States fortreatment of castration resistant or castration sensitive prostatecancer under the brand name Zytiga®. Abiraterone acetate is now alsoavailable globally.

It is known that orally-administered abiraterone acetate is not absorbedby the gastrointestinal tract (and is not detected in blood plasma).Instead, it has been shown that abiraterone acetate is hydrolyzed toabiraterone in the intraluminal environment resulting in generation ofabiraterone supersaturation, which is responsible for creating thestrong driving force for abiraterone absorption (Stappaerts et al., Eur.J. Pharmaceutics Biopharmaceutics 90:1, 2015).

Because abiraterone blocks the normal physiologic production of steroidsby the adrenal glands, its prodrug formulation is commonly prescribedwith administration of a low dose of a steroid to prevent adrenalinsufficiency. Indeed, Zytiga® tablets (250 mg) are approved in theUnited States in combination with prednisone for the treatment ofpatients with metastatic castration resistant prostate cancer andpatients with metastatic castration-sensitive prostate cancer. Theprescribing information provided with Zytiga® recommends oraladministration of 1,000 mg (4×250 mg tablets) once daily in combinationwith prednisone (5 mg) administered orally twice daily for castrationresistant prostate cancer patients or once daily for castrationsensitive prostate cancer patients. In Europe, the use of Zytiga® isapproved in combination with either prednisone or prednisolone.

Because the administration of abiraterone acetate with food increasesthe absorption of abiraterone acetate (and, therefore, has the potentialto result in increased and highly variable exposures, which canpotentially cause various side effects including cardiovascular sideeffects and/or hepatotoxicity etc.), the prodrug should be consumed onan empty stomach at least one hour before, or two hours after, a meal.Indeed, the prescribing information for Zytiga® states it must be takenon an empty stomach, and no food should be consumed for at least twohours before oral dosing and at least one hour after oral dosing.

The prescribing information explains that for a daily oral dose of 1,000mg of Zytiga® in patients with metastatic castration-resistant prostatecancer, abiraterone's steady-state C_(max) values were 226±178 ng/mL(mean±SD) and its area under the curve (AUC) values were 1173±690ng·hr/mL (mean±SD). A single-dose (1,000 mg) cross-over study of Zytiga®in healthy subjects found that systemic exposure of abiraterone wasincreased when Zytiga® was administered with food. Specifically,abiraterone's C_(max) and AUC values were approximately 7- and 5-foldhigher, respectively, when Zytiga® was administered with a low-fat meal(7% fat, 300 calories) and approximately 17- and 10-fold higher,respectively, when Zytiga® was administered with a high-fat meal (57%fat, 825 calories).

The currently approved solid dosage oral form of the prodrug abirateroneacetate has several disadvantages. For example, it has very lowbioavailability that necessitates a large daily pill burden for patients(4×250 mg tablets once daily). In addition, it causes highly variableblood levels in patients due to the combination of low bioavailabilityand a large food effect. Further, as abiraterone is rapidly cleared,this approved dosing regimen results in a daily C_(min) of abiraterone,which is believed to be associated with a loss of therapeutic effect inmetastatic castration resistant prostate cancer patients.

Non-oral modes of administration (for example, parenteral routes) havebeen explored for other classes of drugs. However, to date, there are nosustained-release injectable prodrug formulations of abiraterone.

SUMMARY

In various embodiments, the present disclosure provides novelabiraterone prodrugs, long-acting abiraterone prodrug formulations, andmethods of using the same, for example, in treating a subject having asex hormone-dependent benign or malignant disorder and/or a syndrome dueto androgen and/or glucocorticoid excess. Typically, the novelabiraterone prodrugs herein can be a fatty acid ester of abiraterone,which upon cleavage, releases abiraterone and a safe and degradablefatty acid component. As detailed herein, compared to oral abirateroneacetate formulation, the novel abiraterone prodrugs and formulationsdisclosed herein are a breakthrough in that they provide increasedbioavailability, elimination of the food effect, reduced pill burden,less frequent dosing frequency, and sustained effective blood plasmalevels of abiraterone, e.g., continuous plasma exposures above dailyC_(min) levels observed for oral administration of abiraterone acetate,for example, for at least one week, typically, for at least two weeksfollowing administration of the abiraterone prodrug formulation.Further, pharmacokinetics and pharmacodynamics studies of representativeabiraterone prodrugs herein, such as abiraterone decanoate orabiraterone isocaproate, demonstrate that the novel abiraterone prodrugsand formulations disclosed herein are suitable for dosing once a week,once a month, or even less frequently, for treating a subject having asex hormone-dependent benign or malignant disorder, a syndrome due toandrogen excess and/or a syndrome due to glucocorticoid excess describedherein. This feature alone represents a significant improvement over thecurrently marketed Zytiga® tablets, which require a large daily pillburden for patients (4×250 mg tablets once daily).

Some embodiments of the present disclosure are directed to novelabiraterone prodrugs. In some embodiments, the abiraterone prodrug canbe a compound of Formula I, or a pharmaceutically acceptable saltthereof:

wherein R¹ is defined herein.

In one representative embodiment, an abiraterone prodrug formulation isprovided for parenteral administration to a subject having a sexhormone-dependent benign or malignant disorder, a syndrome due toandrogen excess, and/or a syndrome due to glucocorticoid (e.g.,cortisol) excess. In one aspect, the formulation includes alipophilic-ester form of abiraterone and one or more pharmaceuticallyacceptable carriers, diluents, or excipients (such that, for example,the prodrug formulation is present as a solution or suspension in apharmaceutically acceptable oil, such as an oil of vegetable origin or asynthetic oil including synthetic mono- or di-glycerides of fatty acid;for example, the prodrug formulation can be present as a solution orsuspension in vegetable oil and other co-solvents and excipients). Incertain representative embodiments, the lipophilic-ester form ofabiraterone can be an acetate, propionate, butanoate, valerate,caproate, enanthate, cypionate, isocaproate, buciclate,cyclohexanecarboxylate, phenyl propionate, decanoate or undecanoate. Insome embodiments, the abiraterone prodrug formulation can include acompound of Formula II, or a pharmaceutically acceptable salt thereof:

wherein R² is defined herein. In some embodiments, the abirateroneprodrug formulation can be formulated for intramuscular injection,intradermal injection, or subcutaneous injection. In some embodiments,the compound of Formula II or pharmaceutically acceptable salt thereofcan be present in the formulation at a concentration of about 25 mg/mlto about 500 mg/ml.

Typically, upon administration of a formulation (e.g., the abirateroneprodrug formulation herein), a therapeutic blood plasma concentration ofabiraterone is achieved and persists for at least one week, e.g., atleast two weeks and up to four or more weeks. In one aspect, thetherapeutic blood plasma concentration of abiraterone is at least 1ng/ml, e.g., at least 1 ng/ml, at least 2 ng/ml, at least 4 ng/ml, or atleast 8 ng/ml, following parenteral administration of the prodrugformulation. In some embodiments, the therapeutic blood plasmaconcentration of abiraterone can also be about 0.5 ng/ml or higher.Parenteral administration can be via IM injection, intradermalinjection, or subcutaneous injection. In one aspect, the formulation issuitable for treatment of sex hormone-dependent benign or malignantdisorders such as androgen-dependent disorders and estrogen-dependentdisorders, such as androgen-dependent or estrogen-dependent cancers. Thesex hormone-dependent benign or malignant disorders can include prostatecancer and breast cancer. Prostate cancer can include castrationresistant prostate cancer and castration sensitive prostate cancer. Insome embodiments, the sex hormone-dependent benign or malignantdisorders can include various cancers such as ovarian cancer, bladdercancer, hepatocellular carcinoma, lung cancer, etc. Inhibition ofCYP17A1 is expected to reduce androgen and glucocorticoid (e.g.,cortisole) overproduction. The abiraterone prodrug formulation herein isnot limited to the treatment of oncologic conditions described herein,but can also be used for the treatment of non-oncologic syndromes due toandrogen and glucocorticoid (e.g., cortisole) excess. In one aspect, theformulation is suitable for treatment of non-oncologic syndromes due toandrogen excess, such as endometriosis, polycystic ovary syndrome,congenital adrenal hyperplasia (e.g., classical or nonclassicalcongenital adrenal hyperplasia), precocious puberty, hirsutism, etc.,and/or syndromes due to glucocorticoid (e.g., cortisole) excess such asCushing's syndrome or Cushing's disease.

The parenteral formulations fulfill a long-felt and unmet need byproviding an alternative to oral formulations that suffer from (1) lowbioavailability, (2) interactions with ingested food, (3) delivery ofhighly variable blood levels of parent drug with the possibility ofreduced efficacy and increased side effects, (4) requirement of dailydosing and high pill burden, and (5) poor patient compliance due torequired abstinence from food within hours of administration, high pillburden, and the need for complementary daily administration ofprednisone or prednisolone with a conflicting dosing schedule as it isto be taken with food.

One object of the present disclosure is to provide a method forinhibiting CYP17A1 activity such as inhibiting 17α-hydroxylase activityand 17,20-lyase activity, by parenterally administering to a subject inneed thereof an effective dose of at least one abiraterone prodrugformulation. In some embodiments, the subject suffers from a sexhormone-dependent benign or malignant disorder, a syndrome due toandrogen excess, and/or a syndrome due to glucocorticoid excess such ashypercortisolemia as described herein.

One object of the present disclosure is to provide a method for reducingthe level of glucocorticoids (e.g., cortisol) by parenterallyadministering to a subject in need thereof an effective dose of at leastone abiraterone prodrug formulation. In some embodiments, the subjectsuffers from a syndrome due to glucocorticoid excess, such as due tohypercortisolemia as described herein. In some embodiments, the subjectsuffers from Cushing's syndrome disorders or Cushing's disease.

One object of the present disclosure is to provide a method for reducingthe level of androgens (e.g., testosterone and/or dihydrotestosterone)and/or estrogens by parenterally administering to a subject in needthereof an effective dose of at least one abiraterone prodrugformulation. In some embodiments, the subject suffers from a syndromedue to androgen excess, such as classical or nonclassical congenitaladrenal hyperplasia, endometriosis, polycystic ovary syndrome precociouspuberty, hirsutism, etc. In some embodiments, the subject suffers froman androgen and/or estrogen associated cancer, such as prostate canceror breast cancer.

Another object is to provide a method for treating a sexhormone-dependent benign or malignant disorder, a syndrome due toandrogen excess, and/or a syndrome due to glucocorticoid excess such ashypercortisolemia, by parenterally administering to a subject in need ofsuch treatment an effective dose of at least one abiraterone prodrugformulation. In one representative embodiment, the method is fortreating a sex hormone-dependent benign or malignant disorder, which isan androgen-dependent disorder or an estrogen-dependent disorder, suchas an androgen-dependent cancer or an estrogen-dependent cancer. The sexhormone-dependent benign or malignant disorder can include prostatecancer or breast cancer. Prostate cancer can include castrationresistant prostate cancer and castration sensitive prostate cancer. Insome embodiments, the sex hormone-dependent benign or malignant disordercan also include ovarian cancer, bladder cancer, hepatocellularcarcinoma, lung cancer, etc. In one representative embodiment, themethod is for treating a non-oncologic syndrome due to androgen excess,such as endometriosis, polycystic ovary syndrome, congenital adrenalhyperplasia (e.g., classical or nonclassical congenital adrenalhyperplasia), precocious puberty, hirsutism, etc., and/or a syndrome dueto glucocorticoid (e.g., cortisole) excess such as Cushing's syndrome orCushing's disease.

In some embodiments, the abiraterone prodrug formulation can include atleast one compound of Formula I or II, or a pharmaceutically acceptablesalt thereof. In one aspect, the formulation includes a lipophilic-esterform of abiraterone and one or more pharmaceutically acceptablecarriers, diluents, or excipients. In certain representativeembodiments, the lipophilic-ester form of abiraterone can be, forexample, an acetate, propionate, butanoate, valerate, caproate,enanthate, cypionate, isocaproate, buciclate, cyclohexanecarboxylate,phenyl propionate, decanoate or undecanoate. Upon administration of aformulation to a subject in need thereof, a therapeutic blood plasmaconcentration of abiraterone is achieved and persists for at least oneweek, e.g., at least two weeks and up to four or more weeks. In oneaspect, the therapeutic blood plasma concentration of abiraterone is atleast 1 ng/ml, e.g., at least 1 ng/ml, at least 2 ng/ml, at least 4ng/ml, or at least 8 ng/ml, following parenteral administration of theprodrug formulation. In some embodiments, the therapeutic blood plasmaconcentration of abiraterone can also be about 0.5 ng/ml or higher.Parenteral administration can be via IM injection, intradermalinjection, or subcutaneous injection. In certain embodiments, the methodcan include once-monthly administration of at least one abirateroneprodrug formulation. In one aspect, at least one abiraterone prodrugformulation can be administered in a divided dose. In anotherrepresentative embodiment, at least one abiraterone prodrug formulationcan be administered simultaneously with one or more different prodrugformulations and/or at least one other drug or agent (for example,another cancer chemotherapeutic drug, hormone replacement drug, orhormone ablation drug). In certain aspects, at least one abirateroneprodrug formulation can be administered before at least one other drugor agent. Alternatively, at least one abiraterone prodrug formulationcan be administered after at least one other drug or agent. In otherrepresentative embodiments, more than one administration of one or moreformulations can be performed over the course of several days, weeks,months, or years to provide initial and continual treatment of a sexhormone-dependent benign or malignant disorder (such as prostatecancer), a syndrome due to androgen excess, and/or a syndrome due toglucocorticoid excess such as hypercortisolemia. In other representativeembodiments, at least one abiraterone prodrug formulation can contain atleast two different lipophilic-ester forms of abiraterone and theformulation can be administered simultaneously with one or moredifferent prodrug formulations and/or at least one other drug or agent(for example, another cancer chemotherapeutic drug, hormone replacementdrug, or hormone ablation drug). In certain aspects, at least oneabiraterone prodrug formulation can contain at least two differentlipophilic-ester forms of abiraterone and the formulation can beadministered before at least one other drug or agent. Alternatively, atleast one abiraterone prodrug formulation can contain at least twodifferent lipophilic-ester forms of abiraterone and the formulation canbe administered after at least one other drug or agent. In otherrepresentative embodiments, more than one administration of one or moreformulations containing at least two different lipophilic-ester forms ofabiraterone can be performed over the course of several days, weeks,months, or years to provide initial and continual treatment of a sexhormone-dependent benign or malignant disorder (such as prostatecancer), a syndrome due to androgen excess, and/or a syndrome due toglucocorticoid excess such as hypercortisolemia. The lipophilic-esterforms of abiraterone can be chosen from among, for example, an acetate,propionate, butanoate, valerate, caproate, enanthate, cypionate,isocaproate, buciclate, cyclohexanecarboxylate, phenyl propionate,decanoate or undecanoate.

Another object is to provide a kit for treating a subject with a sexhormone-dependent benign or malignant disorder (such as prostatecancer), a syndrome due to androgen excess, and/or a syndrome due toglucocorticoid excess such as hypercortisolemia. In a representativeembodiment, the kit includes a container such as a vial, an ampule, or apreloaded syringe, containing one or more formulations. In anotherrepresentative embodiment, the kit includes a container such as a vial,an ampule, or a preloaded syringe, containing one or more formulationsand at least one other drug or agent capable of enhancing the efficacyof the formulation(s) or decreasing an undesirable side effect(s) of theformulation(s). In other representative embodiments, the kit includes acontainer such as a vial, an ampule, or a preloaded syringe containingone or more formulations and at least one other drug or agent capable ofenhancing the efficacy of the formulation(s) or decreasing anundesirable side effect(s) of the formulations. It is understood thatthe formulations can contain one lipophilic-ester form of abiraterone ortwo or more different lipophilic-ester forms of abiraterone. A personskilled in the art would understand that kits and packages can beprepared including one, all, or any combination of a formulation,diluent, buffer, adjuvant, pharmaceutically-acceptable carrier, and atleast one other drug or agent capable of enhancing the efficacy of aformulation or decreasing an undesirable side effect of a formulation.

Another object is to provide a method for preparing an abirateronedecanoate formulation suitable for parenteral administration to asubject having a sex hormone-dependent benign or malignant disorder, asyndrome due to androgen excess, and/or a syndrome due to glucocorticoidexcess such as hypercortisolemia.

These and other objects can be achieved in certain embodiments.

In some embodiments, the disclosure provides:

-   -   [1] a compound of Formula I, or a pharmaceutically acceptable        salt thereof,

-   -   -   wherein R¹ is R¹⁰, O—R¹⁰, or NHR¹⁰        -   wherein R¹⁰ is selected from:        -   a C₇₋₃₀ alkyl; a C₇₋₃₀ alkenyl; a C₇₋₃₀ alkynyl; an alkyl            substituted with a cycloalkyl, which has a total number of            carbons between 5 and 16; an alkyl substituted with a            phenyl, which has a total number of carbons between 7 and            16; a cycloalkyl optionally substituted with one or more            alkyl, which has a total number of carbons between 5 and 16;            and

-   -   [2] the compound of [1], or a pharmaceutically acceptable salt        thereof, wherein R¹ is a C₇₋₁₆ alkyl,    -   [3] the compound of [1] or [2], or a pharmaceutically acceptable        salt thereof, wherein R¹ is an alkyl having the formula        —(CH₂)_(n)—CH₃, wherein n is an integer selected from 6, 7, 8,        9, 10, 11, or 12,    -   [4] the compound of [1], or a pharmaceutically acceptable salt        thereof, wherein R¹ is an alkyl having the formula —(CH₂)₈—CH₃        or

-   -   [5] a pharmaceutical composition comprising the compound of any        one of [1]-[4], or a pharmaceutically acceptable salt thereof,        and a pharmaceutically acceptable carrier;    -   [6] a pharmaceutical composition comprising abiraterone        decanoate having the formula of:

-   -   -   or a pharmaceutically acceptable salt thereof, and a            pharmaceutically acceptable carrier,

    -   [7] the pharmaceutical composition of [5] or [6], formulated for        intramuscular injection, intradermal injection, or subcutaneous        injection,

    -   [8] the pharmaceutical composition of any one of [5]-[7],        wherein the pharmaceutically acceptable carrier comprises a        pharmaceutically acceptable oil and optionally a further        pharmaceutically acceptable solvent,

    -   [9] the pharmaceutical composition of [8], wherein the        pharmaceutically acceptable oil comprises a triglyceride (e.g.,        long and/or medium chain triglycerides), and the further        pharmaceutically acceptable solvent, if present, comprises an        alcohol, ester, and/or acid solvent,

    -   [10] the pharmaceutical composition of any one of [8]-[9],        wherein the pharmaceutically acceptable oil is selected from        vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil,        peanut oil (arachis oil), poppy seed oil, tea seed oil, and        soybean oil, and the further pharmaceutically acceptable        solvent, if present, comprises benzyl alcohol, benzyl benzoate,        or a combination thereof,

    -   [11] the pharmaceutical composition of any one of [6]-[10],        which comprises the abiraterone decanoate or pharmaceutically        acceptable salt thereof in an amount sufficient to provide a        therapeutically effective blood plasma concentration of        abiraterone, or a blood plasma concentration of abiraterone of        about 1 ng/ml or higher, for a period of at least two weeks        (e.g., at least three weeks, at least four weeks, and up to six        or eight weeks or more), after a single administration to a        subject having one or more disorders selected from a sex        hormone-dependent benign or malignant disorder, a syndrome due        to androgen excess, and a syndrome to glucocorticoid excess such        as hypercortisolemia,

    -   [12] a method of treating one or more disorders selected from a        sex hormone-dependent benign or malignant disorder, a syndrome        due to androgen excess, and a syndrome to glucocorticoid excess        such as hypercortisolemia, comprising administering to a subject        in need thereof a therapeutically effective amount of the        pharmaceutical composition of any one of [5]-[11],

    -   [13] the method of [12], wherein the administering is an        intramuscular injection, intradermal injection, or subcutaneous        injection,

    -   [14] the method of any one of [12]-[13], wherein the        pharmaceutical composition is administered to the subject with        or without food,

    -   [15] the method of any one of [12]-[14], wherein the one or more        disorders are selected from prostate cancer, breast cancer,        ovarian cancer, bladder cancer, hepatocellular carcinoma, lung        cancer, endometriosis, polycystic ovary syndrome, Cushing's        syndrome, Cushing's disease, classical congenital adrenal        hyperplasia, nonclassical congenital adrenal hyperplasia,        precocious puberty, hirsutism, and combinations thereof.

    -   [16] the method of any one of [12]-[14], wherein the one or more        disorders is a sex hormone-dependent benign or malignant        disorder selected from castration resistant prostate cancer and        castration sensitive prostate cancer,

    -   [17] the method of any one of [12]-[14], wherein the one or more        disorders is a sex hormone-dependent benign or malignant        disorder selected from metastatic castration resistant prostate        cancer and metastatic castration sensitive prostate cancer,

    -   [18] the method of any one of [12]-[17], wherein the subject is        treated with a gonadotropin-releasing hormone analog and/or        bilateral orchiectomy,

    -   [19] the method of any one of [12]-[18], further comprising        administering to the subject a corticosteroid,

    -   [20] the method of any one of [12]-[19], further comprising        administering to the subject prednisone, prednisolone, and/or        methylprednisolone,

    -   [21] the method of any one of [12]-[20], wherein the        pharmaceutical composition is administered to the subject once a        week or once in more than a week, e.g., the dosing frequency        ranges from once a week to once every few months, such as from        once a week to once every eight weeks, or once a week to once        every three months,

    -   [22] the method of any one of [12]-[21], wherein the        administering provides (a) a blood plasma concentration of        abiraterone above 1.0 ng/ml for a period of at least two        weeks; (b) a single dose or steady state C_(max) of abiraterone        between about 10 ng/ml and about 400 ng/ml; or (c) both (a) and        (b),

    -   [23] a pharmaceutical composition, e.g., a unit dosage form,        comprising a therapeutically effective amount of abiraterone        decanoate having the formula of:

a pharmaceutically acceptable oil, and a pharmaceutically acceptablesolvent, wherein the abiraterone decanoate is in its basic form, whichis present at a concentration of about 25 mg/ml to about 500 mg/ml,wherein the pharmaceutical composition, e.g., unit dosage form, isformulated for intramuscular injection, intradermal injection, orsubcutaneous injection, wherein the pharmaceutical composition, e.g.,unit dosage form, comprises the abiraterone decanoate in an amount ofabout 50 mg to about 2,000 mg,

-   -   [24] the pharmaceutical composition, e.g., unit dosage form, of        [23], wherein the pharmaceutically acceptable oil comprises a        triglyceride, and the pharmaceutically acceptable solvent        comprises an alcohol, ester, and/or acid solvent,    -   [25] the pharmaceutical composition, e.g., unit dosage form, of        [23] or [24], wherein pharmaceutically acceptable oil comprises        a vegetable oil, castor oil, corn oil, sesame oil, cottonseed        oil, peanut oil, poppy seed oil, tea seed oil, or soybean oil,        the pharmaceutically acceptable solvent comprises benzyl alcohol        and/or benzyl benzoate, and wherein the abiraterone decanoate is        present at a concentration of about 50 mg/mL to about 300 mg/mL,        such as about 100 mg/mL to about 300 mg/mL,    -   [26] a method of treating prostate cancer, comprising        administering to a subject in need thereof the pharmaceutical        composition, e.g., unit dosage form, of any one of [23]-[25] via        intramuscular injection, intradermal injection, or subcutaneous        injection, once a month or once in more than a month, e.g., the        dosing frequency ranges from once a month to once every few        months, such as from once a month to once every two months, or        from once a month to once every three months, etc.,    -   [27] the method of [26], wherein the pharmaceutical composition,        e.g., unit dosage form, is administered via intramuscular        injection,    -   [28] a method for preparing an abiraterone decanoate        formulation, e.g., suitable for parenteral administration to a        subject having a sex hormone-dependent benign or malignant        disorder, a syndrome due to androgen excess, and/or a syndrome        due to glucocorticoid excess such as hypercortisolemia,        comprising:        -   a) mixing abiraterone decanoate, which has the formula of:

in a pharmaceutically acceptable carrier to form a mixture; andoptionally

-   -   -   b) sterilizing the mixture formed in a),

    -   [29] the method of [28], wherein the mixing comprises mixing a        crystalline form of abiraterone decanoate in the        pharmaceutically acceptable carrier, wherein the crystalline        form is characterized by an X-Ray Power Diffraction (XRPD)        spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9)        of the following peaks: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1,        19.6, and 20.8, degrees 2 theta, ±0.2°; a Differential Scanning        Calorimetry (DSC) pattern having an endothermic peak with an        onset temperature at about 69.0° C.; or a combination thereof,

    -   [30] the method of [28] or [29], wherein the pharmaceutically        acceptable carrier comprises a pharmaceutically acceptable oil        and a pharmaceutically acceptable solvent, wherein the        pharmaceutically acceptable oil comprises a vegetable oil,        castor oil, corn oil, sesame oil, cottonseed oil, peanut oil,        poppy seed oil, tea seed oil, or soybean oil, the        pharmaceutically acceptable solvent comprises benzyl alcohol or        benzyl benzoate, and wherein the abiraterone decanoate is        present at a concentration of about 50 mg/mL to about 300 mg/mL,        such as about 100 mg/mL to about 300 mg/mL.

Embodiments of the present disclosure can fulfill a long felt need inthe field of sex hormone-dependent disorders and oncology including thechemotherapy of prostate cancer. Embodiments of the present disclosurecan also fulfill a long felt need in the field of treating syndromes dueto androgen excess syndrome and/or due to glucocorticoid excess such ashypercortisolemia. Embodiments of the present disclosure can overcomemajor disadvantages and deficiencies of prior art formulations(including commercially-available oral dosage forms) of abirateroneacetate, by providing long-acting, sustained release depot-basedparenteral formulations of abiraterone prodrugs, methods of producingthe same, methods of treatment using the same, and kits for convenientadministration of the formulations to subjects in need of therapy forvarious disorders including prostate cancer.

There has thus been outlined, rather broadly, features in order that thedetailed description thereof that follows may be better understood, andin order that the present contribution to the art may be betterappreciated. There are, of course, additional features that will bedescribed further hereinafter. Indeed, it is to be understood that boththe foregoing general description and the following detailed descriptionare exemplary and explanatory and are intended to provide furtherexplanation of the disclosure.

In this respect, before explaining at least one embodiment in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and to the arrangements of the componentsset forth in the following description or illustrated in the drawings.The invention is capable of other embodiments and of being practiced andcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein are for the purpose ofdescription and should not be regarded as limiting.

As such, those persons skilled in the art will appreciate that theconception upon which this disclosure is based can readily be utilizedas a basis for the designing of other formulations, methods, systems,kits, and compositions for carrying out the several purposes of thepresent disclosure. It is important, therefore, that equivalentconstructions insofar as they do not depart from the spirit and scope ofthe present disclosure, are included in the present disclosure.

The accompanying drawings are included to provide a furtherunderstanding and are incorporated in and constitute a part of thisspecification, illustrate several embodiments, and together with thedescription serve to explain the principles.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean blood plasma concentrations of abiraterone (ng/ml)in rats at different times (hours) after IM administration of variousabiraterone or abiraterone acetate formulations. FIG. 1 shows theprofile obtained with abiraterone acetate solution in castor oil (70mg/ml); the profile obtained with abiraterone acetate suspension, sodiumphosphate buffer, 0.1% Tween (70 mg/ml); the profile obtained withabiraterone suspension in castor oil (62.5 mg/ml) and the profileobtained with abiraterone suspension, sodium phosphate buffer, 0.1%Tween (62.5 mg/ml).

FIG. 2 shows the mean blood plasma concentrations of abiraterone (ng/ml)in dogs at different times (hours) after IM or intravenous (IV)administration of various abiraterone acetate formulations. FIG. 2 showsthe profile obtained with IV administration of abiraterone acetatesolution (33% aq HP-beta-cyclodextrin) dosed at 10 mg/kg; the profileobtained with IM administration of abiraterone acetate solution incastor oil (66 mg/ml) dosed at 21 mg/kg; the profile obtained with IMadministration of abiraterone acetate solution in castor oil with 10%benzyl alcohol (91 mg/ml) dosed at 30 mg/kg and the profile obtainedwith IM administration of abiraterone acetate solution in castor oilwith 50% benzyl benzoate (124 mg/ml) dosed at 42 mg/kg.

FIG. 3 shows the mean blood plasma concentrations of abiraterone (topline) and abiraterone acetate (bottom line) (ng/ml) in dogs at differenttimes (hours) after IV administration of abiraterone acetate (dosed at10.3 mg/ml as a solution in 33% aqueous HP-beta-cyclodextrin).

FIG. 4 shows the mean blood plasma concentration of abiraterone (topline) and abiraterone acetate (bottom line) (ng/nl) in dogs at differenttimes (days) after IM administration of abiraterone acetate solution incastor oil with 10% benzyl alcohol (91 mg/ml) dosed at 30 mg/kg.

FIG. 5 shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following IV administration of1.2 mg/kg abiraterone decanoate in dogs. Error bars represent standarddeviation.

FIG. 6 shows mean abiraterone and abiraterone propionate plasmaconcentration versus time profile data following IV administration of 1mg/kg abiraterone propionate in dogs. Error bars represent standarddeviation.

FIG. 7 shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following IM Administration of 50mg/kg abiraterone decanoate (90% castor oil/10% benzyl alcohol) in dogs.Error bars represent standard deviation.

FIG. 8 shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following IM Administration of 50mg/kg abiraterone decanoate (90% corn oil/10% benzyl alcohol) in dogs.Error bars represent standard deviation.

FIG. 9 shows mean abiraterone and abiraterone propionate plasmaconcentration versus time profile data following IM administration of 41mg/kg abiraterone propionate (90% castor oil/10% benzyl alcohol) indogs. Error bars represent standard deviation.

FIG. 10 shows mean abiraterone and abiraterone propionate plasmaconcentration versus time profile data following IM administration of 41mg/kg abiraterone propionate (90% corn oil/10% benzyl alcohol) in dogs.Error bars represent standard deviation.

FIG. 11A, FIG. 11B, FIG. 11C, and FIG. 11D show exemplary predictedhuman abiraterone plasma concentrations following intramuscularadministration of abiraterone decanoate by computer modeling in human,using an input half-life assumed to be the same as that observed in dog.FIG. 11A shows a computer modeling prediction following an IM dose of120 mg abiraterone decanoate every two weeks and FIG. 11B shows acomputer modeling prediction following an IM dose of 350 mg abirateronedecanoate every four weeks. FIG. 11C shows a computer modelingprediction following an IM dose of 1000 mg abiraterone decanoate everysix weeks. FIG. 11D shows a computer modeling prediction following an IMdose of 1700 mg abiraterone decanoate every two months. The horizontallines in FIG. 11A, FIG. 11B, FIG. 11C, and FIG. 11D represent a targetedC_(min) value of abiraterone of about 8 ng/ml.

FIG. 12A presents a representative X-ray Powder Diffraction (XRPD)spectrum of the abiraterone decanoate solid form prepared in Example 6A.

FIG. 12B shows a Differential Scanning Calorimetry (DSC) spectrum of theabiraterone decanoate solid form prepared in Example 6A.

FIG. 12C shows a thermogravimetric analysis (TGA) of the abirateronedecanoate solid form prepared in Example 6A.

FIG. 13A presents a plot of abiraterone decanoate solubility in corn oilin the presence of various amounts of benzyl alcohol and benzylbenzoate. FIG. 13B shows a contour plot of abiraterone decanoatesolubility in corn oil in the presence of various amounts of benzylalcohol and benzyl benzoate. FIG. 13C shows viscositiy (Pa*s) forvarious oil vehicles, without additive or with 10% benzyl alcohol, 20%benzyl benzoate, or a combination of 10% benzyl alcohol and 20% benzylbenzoate. FIGS. 13D and 13E show Glide Foce (N) for various oilvehicles, without additive or with 10% benzyl alcohol, 20% benzylbenzoate, or a combination of 10% benzyl alcohol and 20% benzyl benzoatetested with 5 ml Syringe, with 23 Gauge needle or 27 Gauge needle,respectively.

FIG. 14A shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following IV administration of1.2 mg/kg abiraterone decanoate (0.4 mg/ml solution in 40%HP-beta-cyclodextrin 25 mM Na phosphate buffer (pH 7.4)) in MaleCynomolgus Monkeys (n=3).

FIG. 14B shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following a single IMadministration of abiraterone decanoate formulation (90% Corn Oil, 10%Benzyl Alcohol, 192 mg/ml abiraterone decanoate) at a dose of 90 mg/kgabiraterone decanoate in Male Cynomolgus Monkeys (n=3). FIG. 14C showsthe observed steroid levels (progesterone, cortisol and testosteronelevels) versus time profile data following this single dose IMadministration. As shown in FIG. 14C, following the single dose IMinjection, a long duration of CYP17A1 inhibition was achieved asevidenced by the sustained increase of progesterone level and reductionof glucocorticoid (cortisol) and sex hormone (testosterone) level. FIG.14D presents biochemical pathways showing the effects of CYP17A1inhibition on the synthesis of androgens, estrogens, glucocorticoids,progesterone and mineralocorticoids. As shown in FIG. 14D, inhibition ofCYP17A1 17α-hydroxylase and C17,20-lyase activities will lead to (1)increases in levels of progesterone and the mineralocorticoids; (2)reductions in levels of glucocorticoids such as cortisol; and (3)reductions in levels of sex hormones, e.g., androgens such astestosterone and dihydrotestosterone, and estrogens such as estradiol.

FIG. 14E shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following multiple doses of IMadministration of abiraterone decanoate formulation (90% Corn Oil, 10%Benzyl Alcohol, 192 mg/ml abiraterone decanoate) in Male CynomolgusMonkeys (n=3) at Day 0, Day 7 and Day 35. Each dose is of 90 mg/kgabiraterone decanoate.

FIG. 14F shows mean abiraterone plasma concentration versus time profiledata following multiple doses of IM administration of abirateronedecanoate Formulation 1 (90% Corn Oil, 10% Benzyl Alcohol, 207 mg/mlabiraterone decanoate) or Formulation 2 (70% Corn Oil, 10% BenzylAlcohol, 20% benzyl benzoate, 209 mg/ml abiraterone decanoate) in MaleCynomolgus Monkeys (n=1) at Day 0, Day 7 and Day 14. Each dose is of 100mg/kg abiraterone decanoate.

FIG. 15A shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following IV administration of1.2 mg/kg abiraterone decanoate (0.4 mg/ml solution in 40%HP-beta-cyclodextrin 25 mM Na phosphate buffer (pH 7.4)) in Male Rats(n=5).

FIG. 15B shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following a single IMadministration of abiraterone decanoate formulation (90% Corn Oil, 10%Benzyl Alcohol, 172 mg/ml abiraterone decanoate) at a dose of 90 mg/kgabiraterone decanoate in Male Rats (n=5).

FIG. 15C shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following multiple doses of IMadministration of abiraterone decanoate formulation (90% Corn Oil, 10%Benzyl Alcohol, 172 mg/ml abiraterone decanoate) in Male Rats (n=5) atDay 0, Day 7 and Day 35. Each dose is of 90 mg/kg abiraterone decanoate.

FIG. 16A shows allometric scaling of distribution volume (Vss) ofabiraterone in rats, dogs and monkeys, with prediction in man.

FIG. 16B shows predicted plasma profile of abiraterone in man followinga single intramuscular dose of abiraterone at 1 mg based on abioavailability of 56%.

FIG. 16C shows predicted plasma profile of abiraterone in man followingrepeated intramuscular doses of abiraterone decanoate at 1000 mg every 4weeks based on a bioavailability of 56%.

FIG. 16D shows predicted plasma profile of abiraterone in man followingrepeated intramuscular doses of abiraterone decanoate at 1000 mg every 4weeks assuming complete bioavailability.

FIG. 17A shows mean abiraterone and abiraterone isocaproate plasmaconcentration versus time profile data following IV administration of1.0 mg/kg abiraterone isocaproate in dogs. Error bars represent standarddeviation.

FIG. 17B shows mean abiraterone and abiraterone isocaproate plasmaconcentration versus time profile data following IM administration ofabiraterone isocaproate in dogs. Error bars represent standarddeviation.

FIG. 17C shows mean abiraterone and abiraterone decanoate plasmaconcentration versus time profile data following IM administration ofabiraterone decanoate in dogs. Error bars represent standard deviation.

FIG. 17D shows mean abiraterone plasma concentration versus time profiledata following IM administration of abiraterone isocaproate or decanoatein dogs. Error bars represent standard deviation.

DETAILED DESCRIPTION

The present disclosure relates to compounds and compositions thatdeliver therapeutic blood plasma levels of the active drug abirateroneover an extended period of time to subjects. Initial experiments in therat determined that injecting suspensions of the active drug abirateroneintramuscularly did not achieve the desired therapeutic blood plasmalevels. However, as detailed herein, it was found that representativenovel abiraterone prodrugs and formulations, when administeredparenterally (e.g., intramuscularly), achieved desired therapeutic bloodplasma levels for a prolonged period of time.

Accordingly, various embodiments of the present disclosure are directedto such novel abiraterone prodrugs and formulations, which can havevarious advantages over existing abiraterone formulations, such as themarketed oral abiraterone acetate formulation. Such advantages include,but are not limited to, improved bioavailability, elimination of thefood effect associated with oral abiraterone acetate formulation,reduced pill burden, better patient compliance, decreased dosingfrequency, sustained stable blood levels of active drug, reducedC_(max), which can reduce associated side effects, etc. In someembodiments, methods of using the novel abiraterone prodrugs andformulations are also provided, for example, for treating sexhormone-dependent benign or malignant disorders (such as prostatecancer), syndromes due to androgen excess, and/or syndromes due toglucocorticoid excess such as hypercortisolemia.

Compounds of Formula I

In some embodiments, the present disclosure provides a novel abirateroneprodrug. In some embodiments, the novel abiraterone prodrug is acompound of Formula I, or a pharmaceutically acceptable salt thereof:

Various groups are suitable as R¹ in Formula I. In some embodiments, R¹can be selected such that the compound of Formula I is an ester (e.g., alipophilic ester), a carbamate, or a carbonate of abiraterone. In someembodiments, R¹ is R¹⁰, O—R¹⁰, or NHR¹⁰, wherein R¹⁰ is selected from: aC₇₋₃₀ alkyl; C₇₋₃₀ alkenyl; C₇₋₃₀ alkynyl; an alkyl substituted with acycloalkyl, which typically has a total number of carbons between 5 and16; an alkyl substituted with a phenyl, which typically has a totalnumber of carbons between 7 and 16; a cycloalkyl optionally substitutedwith one or more alkyl, which typically has a total number of carbonsbetween 5 and 16; and a branched C5 or C6 alkyl such as

In some preferred embodiments, R¹⁰ is a C₇₋₃₀ alkyl. As used herein,unless expressly stated to be substituted, an alkyl should be understoodas unsubstituted. However, an alkyl can be either linear or branched. Insome embodiments, R¹⁰ can be a linear C₇₋₃₀ alkyl. In some embodiments,R¹⁰ can be a branched C₇₋₃₀ alkyl. In some embodiments, R¹⁰ is a linearC₇₋₁₆ alkyl, for example, R¹⁰ can have a formula —(CH₂)_(n)—CH₃, whereinn is an integer between 6 and 15 (e.g., between 6 and 12, such as 6, 7,8, 9, 10, 11, or 12). In some embodiments, R¹⁰ can be a branched C₇₋₁₆alkyl.

In some embodiments, R¹⁰ can also be an alkyl substituted with acycloalkyl. Typically, in such embodiments, R¹⁰ has a total number ofcarbons between 5 and 16, i.e., the total number of carbons from thealkyl moiety and the cycloalkyl moiety are between 5 and 16. Thecycloalkyl typically is unsubstituted. However, in some embodiments, thecycloalkyl can be optionally substituted, e.g., with one or two loweralkyl (e.g, a C₁₋₄ alkyl). In some embodiments, R¹⁰ can be an alkylsubstituted with a C₃₋₆ cycloalkyl, which typically has a total numberof carbons between 6 and 12. In some embodiments, R¹⁰ can be a linearalkyl substituted with a C₃₋₆ cycloalkyl, for example, R¹⁰ can have aformula —(CH₂)_(n)-Cy, wherein n is an integer of 1-6 (e.g., 1, 2, 3, 4,5, or 6), and Cy is a C₃₋₆ cycloalkyl (such as cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl). In some embodiments, R¹⁰ can have a formula—(CH₂)_(n)-Cy, wherein n is 1 or 2, and Cy is cyclopentyl or cyclohexyl.In some embodiments, R¹⁰ can also be a branched alkyl (e.g., branchedC₂₋₆) substituted with a C₃₋₆ cycloalkyl. As used herein, a branched C2alkyl should be understood as a 1,1-disubstituted ethyl group, forexample, —CH(CH₃)-Cy.

In some embodiments, R¹⁰ can also be an alkyl substituted with a phenyl.Typically, in such embodiments, R¹⁰ has a total number of carbonsbetween 7 and 16, i.e., the total number of carbons from the alkylmoiety and the phenyl moiety are between 5 and 16. In some embodiments,R¹⁰ can be a linear alkyl substituted with a phenyl, for example, R¹⁰can have a formula —(CH₂)_(n)-Cy, wherein n is an integer of 1-6 (e.g.,1, 2, 3, 4, 5, or 6), and Cy is a phenyl. In some embodiments, R¹⁰ canhave a formula —(CH₂)_(n)-Cy, wherein n is 1 or 2, and Cy is phenyl. Insome embodiments, R¹⁰ can also be a branched alkyl (e.g., branched C₂₋₆)substituted with a phenyl. The phenyl typically is unsubstituted.However, in some embodiments, the phenyl can be optionally substituted,e.g., with one or two lower alkyl (e.g, a C₁₋₄ alkyl).

In some embodiments, R¹⁰ can be a cycloalkyl optionally substituted withone or more alkyl. In such embodiments, R¹⁰ typically has a total numberof carbons between 5 and 16, i.e., the total number of carbons of thecycloalkyl and its optional substituents are between 5 and 16. In someembodiments, R¹⁰ can be a C₃₋₆ cycloalkyl, either unsubstituted orsubstituted with a C₁₋₄ alkyl. In some specific embodiments, R¹⁰ can be

or

In some embodiments, R¹⁰ can be a branched C5 or C6 alkyl. In someembodiments, R¹⁰ can be

Other branched C5 or C6 alkyls are also suitable.

In some embodiments, R¹⁰ can be an unsaturated aliphatic group such as aC₇₋₃₀ alkenyl or a C₇₋₃₀ alkynyl.

In some preferred embodiments, the compound of Formula I is an ester ofabiraterone, e.g., R¹ is R¹⁰, wherein R¹⁰ is defined herein. In someembodiments, R¹ in Formula I can be a C₇₋₁₆ alkyl, e.g., an alkyl havinga formula of —(CH₂)_(n)—CH₃, wherein n is an integer between 6 and 12(e.g., 6, 7, 8, 9, 10, 11, or 12). In some embodiments, R¹ in Formula Ican be represented by the formula —(CH₂)_(n)-Cy, wherein n is an integerof 1-6, and Cy is a C₃₋₆ cycloalkyl or phenyl, for example, in morespecific embodiments, n can be 1 or 2, and Cy is cyclopentyl,cyclohexyl, or phenyl. In some specific embodiments, R¹ in Formula I canbe

In some specific embodiments, R¹ in Formula I can be

or

Other suitable groups for R include any of the R¹⁰ defined herein.

In some embodiments, R¹ in Formula I can also be O—R¹⁰ or NHR¹⁰, whereinR¹⁰ is defined herein.

Typically, compounds of Formula I can be present in a formulation in thebasic form, for example, in a non-aqueous formulation. However, in someembodiments, pharmaceutically acceptable salts of compounds of Formula Iare also useful. Unless specifically referred to as in its salt form orotherwise contradictory from context, the compound of Formula I can bein its basic form in the abiraterone prodrug formulations describedherein.

Compounds of Formula I can be readily synthesized by those skilled inthe art in view of the present disclosure. Exemplary synthesis ofrepresentative compounds are described in the Examples section. Forexample, typically, esters of Formula I can be prepared by reactingabiraterone with a corresponding carboxylic acid, or an activated formthereof, such as the corresponding acyl chloride, anhydride, etc.Exemplary reaction conditions using an activated form such as acylchloride are shown in the Examples section.

Abiraterone Prodrug Formulations

Abiraterone prodrugs herein, including compounds of Formula I, areuseful for delivering abiraterone to a subject in need thereof, forexample, to a subject having a sex hormone-dependent benign or malignantdisorder, a syndrome due to androgen excess, and/or a syndrome due toglucocorticoid excess such as hypercortisolemia herein. Typically, theabiraterone prodrugs can be formulated as a parenteral formulation, suchas an intramuscular, intradermal, or subcutaneous formulation, and canin some embodiments be formulated to deliver a therapeutically effectiveplasma concentration of abiraterone over an extended period of time,e.g., for at least 1 week, at least 2 weeks, at least 3 weeks, at least4 weeks, and up to six or eight weeks or more, etc.

Various abiraterone prodrugs, such as abiraterone esters, carbamates, orcarbonates are suitable for compositions and methods of the presentdisclosure. In some embodiments, the present disclosure provides apharmaceutical composition (alternatively sometimes referred to asabiraterone prodrug formulation herein) comprising a compound of FormulaI (e.g., any one or more as defined herein), or a pharmaceuticallyacceptable salt thereof. In some embodiments, the pharmaceuticalcomposition can be formulated for parenteral administration, such asintramuscular injection, intradermal injection, or subcutaneousinjection. The pharmaceutical composition typically includes apharmaceutically acceptable carrier. Suitable carriers include thoseknown in the art, for example, those described in “Remington: TheScience and Practice of Pharmacy” (formerly “Remington's PharmaceuticalSciences,” University of the Sciences in Philadelphia, Lippincott,Williams & Wilkins, Philadelphia, Pa. (2005)) and the U.S. Food and DrugAdministration's Center for Drug Evaluation and Research's database ofinactive ingredients present in FDA-approved drugs. In some embodiments,the pharmaceutically acceptable carrier can be a carrier that isapproved for use by the FDA for an intramuscular, intradermal, orsubcutaneous drug product, e.g., those listed in the FDA's database ofinactive ingredients. In some embodiments, the pharmaceuticallyacceptable carrier can be any suitable nonaqueous vehicle suitable forinjection, such as those described in U.S. Pharmacopeia. In someembodiments, the pharmaceutically acceptable carrier can be apharmaceutically acceptable oil, e.g., a vegetable oil, castor oil, cornoil, sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seedoil, or soybean oil. In some embodiments, the pharmaceuticallyacceptable oil can be oils (e.g., described herein) suitable for use asvehicles for injection, e.g., meeting the criteria as described in thecorresponding U.S. Pharmacopeia monograph. In some embodiments, thepharmaceutically acceptable oil can be an oil of vegetable originsuitable for use as vehicles for injection. In some embodiments, thepharmaceutically acceptable oil can be a synthetic oil suitable for useas vehicles for injection, such as a synthetic mono- or diglycerides offatty acids, e.g., those that are liquid and remain clear when cooled to10° C. and have an Iodine Value of not more than 140. In someembodiments, the pharmaceutically acceptable oil can be nature oil,synthetic oil, or semi-synthetic oil, such as fractionated coconut oiland medium-chain triglycerides, such as those sold under the trademarkMiglyol. In some embodiments, the pharmaceutically acceptable carriercomprises a triglyceride derived from fatty acids. In some embodiments,the pharmaceutically acceptable carrier comprises a triglyceride derivedfrom long and/or medium chain fatty acids, which can be independentlypoly-unsaturated, mono-unsaturated, or saturated. In some embodiments,two or more different pharmaceutically acceptable oil can be used. Insome embodiments, the pharmaceutical composition is a non-aqueoussolution or suspension. In some embodiments, the pharmaceuticalcomposition further comprises a pharmaceutically acceptable solvent,such as benzyl alcohol. In some embodiments, the compound of Formula Ior pharmaceutically acceptable salt thereof can be present in thepharmaceutical composition at a concentration of about 25 mg/ml to about500 mg/ml (e.g., about 25 mg/ml, about 50 mg/ml, about 100 mg/ml, about150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300 mg/ml, about 400mg/ml, about 500 mg/ml, or any range between the recited values).

In some embodiments, the present disclosure also provides apharmaceutical composition (alternatively sometimes referred to asabiraterone prodrug formulation herein) comprising a compound of FormulaII, or a pharmaceutically acceptable salt thereof.

wherein R² is defined herein. In some embodiments, the pharmaceuticalcomposition can be formulated for intramuscular injection, intradermalinjection, or subcutaneous injection. In some embodiments, the compoundof Formula II or pharmaceutically acceptable salt thereof can be presentin the pharmaceutical composition at a concentration of about 25 mg/mlto about 500 mg/ml (e.g., about 25 mg/ml, about 50 mg/ml, about 100mg/ml, about 150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300mg/ml, about 400 mg/ml, about 500 mg/ml, or any range between therecited values). In some embodiments, the pharmaceutical composition isa non-aqueous solution or suspension. In some embodiments, the compoundof Formula II or pharmaceutically acceptable salt thereof is dissolvedor suspended in a pharmaceutically acceptable oil (e.g., describedherein), such as a vegetable oil, castor oil, corn oil, sesame oil,cottonseed oil, peanut oil, poppy seed oil, tea seed oil, or soybeanoil. In some embodiments, the pharmaceutical composition furthercomprises a pharmaceutically acceptable solvent, such as benzyl alcohol.

Various groups are suitable as R² in Formula II. In some embodiments, R²can be selected such that the compound of Formula II is an ester, acarbamate, or a carbonate of abiraterone. In some embodiments, R² isR²⁰, O—R²⁰, or NHR²⁰, and R²⁰ is selected from: a C₁₋₃₀ alkyl; a C₂₋₃₀alkenyl; a C₂₋₃₀ alkynyl; an alkyl substituted with a cycloalkyl, whichtypically has a total number of carbons between 4 and 30; an alkylsubstituted with a phenyl, which typically has a total number of carbonsbetween 7 and 30; and a cycloalkyl optionally substituted with one ormore alkyl, which typically has a total number of carbons between 3 and30.

In some preferred embodiments, R²⁰ is a C₁₋₁₆ alkyl. In someembodiments, R²⁰ can be a linear C₁₋₁₆ alkyl. In some embodiments, R²⁰can be a branched C₃₋₁₆ alkyl. In some embodiments, R²⁰ can be abranched C5 or C6 alkyl. In some embodiments, R²⁰ can be

In some embodiments, R²⁰ can have a formula —(CH₂)_(n)—CH₃, wherein n isan integer between 0 and 12 (e.g., between 6 and 12, such as 6, 7, 8, 9,10, 11, or 12).

In some embodiments, R²⁰ can also be an alkyl substituted with acycloalkyl. Typically, in such embodiments, R²⁰ has a total number ofcarbons between 4 and 30, such as between 5 and 16 (i.e., the totalnumber of carbons from the alkyl moiety and the cycloalkyl moiety arebetween 5 and 16). The cycloalkyl typically is unsubstituted. However,in some embodiments, the cycloalkyl can be optionally substituted, e.g.,with one or two lower alkyl (e.g, a C₁₋₄ alkyl). In some embodiments,R²⁰ can be an alkyl substituted with a C₃₋₆ cycloalkyl, which typicallyhas a total number of carbons between 6 and 12. In some embodiments, R²⁰can be a linear alkyl substituted with a C₃₋₆ cycloalkyl, for example,R²⁰ can have a formula —(CH₂)_(n)-Cy, wherein n is an integer of 1-6(e.g., 1, 2, 3, 4, 5, or 6), and Cy is a C₃₋₆ cycloalkyl (such ascyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In someembodiments, R²⁰ can have a formula —(CH₂)_(n)-Cy, wherein n is 1 or 2,and Cy is cyclopentyl or cyclohexyl. In some embodiments, R²⁰ can alsobe a branched alkyl (e.g., branched C₂-6) substituted with a C₃₋₆cycloalkyl.

In some embodiments, R²⁰ can also be an alkyl substituted with a phenyl.Typically, in such embodiments, R²⁰ has a total number of carbonsbetween 7 and 30, e.g., between 7 and 16 (i.e., the total number ofcarbons from the alkyl moiety and the phenyl moiety are between 7 and16). In some embodiments, R²⁰ can be a linear alkyl substituted with aphenyl, for example, R²⁰ can have a formula —(CH₂)_(n)-Cy, wherein n isan integer of 1-6 (e.g., 1, 2, 3, 4, 5, or 6), and Cy is a phenyl. Insome embodiments, R²⁰ can have a formula —(CH₂)_(n)-Cy, wherein n is 1or 2, and Cy is phenyl. In some embodiments, R²⁰ can also be a branchedalkyl (e.g., branched C₂-6) substituted with a phenyl. The phenyltypically is unsubstituted. However, in some embodiments, the phenyl canbe optionally substituted, e.g., with one or two lower alkyl (e.g, aC₁₋₄ alkyl).

In some embodiments, R²⁰ can be a cycloalkyl optionally substituted withone or more alkyl. In such embodiments, R²⁰ typically has a total numberof carbons between 3 and 30, e.g., 5 and 16 (i.e., the total number ofcarbons of the cycloalkyl and its optional substituents are between 5and 16). In some embodiments, R²⁰ can be a C₃₋₆ cycloalkyl, eitherunsubstituted or substituted with a C₁₋₄ alkyl. In some specificembodiments, R²⁰ can be

or

In some embodiments, R²⁰ can be an unsaturated aliphatic group such as aC₂₋₃₀ alkenyl or a C₂₋₃₀ alkynyl.

In some preferred embodiments, the compound of Formula II is anabiraterone ester, e.g., R² is R²⁰, wherein R²⁰ is defined herein. Insome embodiments, R² in Formula II can be a C₁₋₁₆ alkyl, e.g., an alkylhaving a formula of —(CH₂)_(n)—CH₃, wherein n is an integer between 0and 12. In some embodiments, R² in Formula II can be represented by theformula —(CH₂)_(n)-Cy, wherein n is an integer of 1-6, and Cy is a C₃₋₆cycloalkyl or phenyl, for example, in more specific embodiments, n canbe 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl. In somespecific embodiments, R² in Formula II can be

or

Other suitable groups for R² include any of the R²⁰ defined herein. Insome embodiments, the abiraterone ester can be an acetate, a propionate,a butanoate, a (vaterate) pentanoate, an isocaproate, a buciclate, acyclohexanecarboxylate, a phenyl propionate, caproate (hexanoate), aenanthate (heptanoate), a cypionate, an octanoate, a noncanoate, adecanoate, an undecanoate, a dodecanoate, a tridecanoate, atetradecanoate, a pentadecanoates, or a hexadecanoate of abiraterone. Insome embodiments, the abiraterone ester can be abiraterone acetate,abiraterone propionate, and abiraterone decanoate. In some specificembodiments, the abiraterone ester can be abiraterone pentanoate,abiraterone hexanoate, abiraterone heptanoate, abiraterone decanoate,abiraterone isocaproate, or abiraterone cypionate.

In some embodiments, R² in Formula II can also be O—R²⁰ or NHR²⁰,wherein R²⁰ is defined herein.

Typically, compounds of Formula II can be present in a formulation inthe basic form, for example, in a non-aqueous formulation. However, insome embodiments, pharmaceutically acceptable salts of compounds ofFormula II are also useful. Unless specifically referred to as in itssalt form or otherwise contradictory from context, the compound ofFormula II can be in its basic form in the abiraterone prodrugformulations described herein.

Compounds of Formula II can be readily synthesized by those skilled inthe art in view of the present disclosure. Exemplary synthesis ofrepresentative compounds are described in the Examples section. Forexample, typically, esters of Formula II can be prepared by reactingabiraterone with a corresponding carboxylic acid, or an activated formthereof, such as the corresponding acyl chloride, anhydride, etc.Exemplary reaction conditions using an activated form such as acylchloride are shown in the Examples section.

Typically, the abiraterone prodrugs of the present disclosure areformulated as a non-aqueous solution or suspension. In some embodiments,the non-aqueous solution or suspension provides higher levels ofabiraterone in the plasma for a longer duration, when compared to anaqueous solution or suspension. For example, as detailed herein, IMinjections of an aqueous suspension and a vegetable oil solution of theabiraterone acetate prodrug were evaluated in rats. Surprisingly, it wasdetermined that the vegetable oil solution (but not the aqueoussuspension) of abiraterone acetate prodrug gave the highest blood plasmalevels and also the longest duration of exposure of active drugabiraterone (see FIG. 1). Accordingly, in some embodiments, theabiraterone prodrug formulations herein can include an abirateroneprodrug of the present disclosure (e.g., compound of Formula I or II)dissolved or dispersed in a pharmaceutically acceptable carrier. In someembodiments, the pharmaceutically acceptable carrier can be any suitablenonaqueous vehicle suitable for injection, such as those described inU.S. Pharmacopeia. In some embodiments, the pharmaceutically acceptablecarrier can be a pharmaceutically acceptable oil, e.g., a vegetable oil,castor oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy seedoil, tea seed oil, or soybean oil. In some embodiments, thepharmaceutically acceptable oil can be oils (e.g., described herein),suitable for use as vehicles for injection, e.g., meeting the criteriaas described in the corresponding U.S. Pharmacopeia monograph. In someembodiments, the pharmaceutically acceptable oil can be an oil ofvegetable origin suitable for use as vehicles for injection. In someembodiments, the pharmaceutically acceptable oil can be a synthetic oilsuitable for use as vehicles for injection, such as synthetic mono- ordiglycerides of fatty acids, e.g., those that are liquid and remainclear when cooled to 10° C. and have an Iodine Value of not more than140. In some embodiments, the pharmaceutically acceptable oil can benature oil, synthetic oil, or semi-synthetic oil, such as fractionatedcoconut oil and medium-chain triglycerides, such as those sold under thetrademark Miglyol. In some embodiments, the pharmaceutically acceptablecarrier comprises a triglyceride derived from fatty acids. In someembodiments, the pharmaceutically acceptable carrier comprises atriglyceride derived from long and/or medium chain fatty acids, whichcan be independently poly-unsaturated, mono-unsaturated, or saturated.In some embodiments, the pharmaceutically acceptable oil can be any ofthose that are approved for use by the FDA for an intramuscular,intradermal, or subcutaneous drug product, e.g., those listed in theFDA's database of inactive ingredients. In some specific embodiments,the pharmaceutically acceptable oil is castor oil or corn oil. In someembodiments, two or more different pharmaceutically acceptable oil canbe used.

Other ingredients can also be optionally included in the abirateroneprodrug formulations herein. In some embodiments, the abirateroneprodrug formulation can further comprise a pharmaceutically acceptablesolvent, such as benzyl alcohol, benzyl benzoate, ethanol, glycerol,polyethylene glycol, polysorbate 80, acetic acid, and ethyl acetate. Itwas determined that the additives/co-solvents benzyl alcohol and benzylbenzoate had the advantage of increasing the solubility of the prodrugsas well as reducing the viscosity and/or glide force of the solution,see e.g., FIGS. 13A-13E and Tables 2A-2D, which provided a moreconcentrated solution that was easier to inject through an acceptablegauge needle for IM injection (e.g., 20-27 gauge such as 22-25 gauge).The co-solvent can be selected based on its ability to reduce theviscosity of the vehicle to allow injection through suitable injectionneedles or cannula. Benzyl alcohol as an additive in IM or subcutaneousinjections also has the advantage that it can act as a local anestheticat the injection site (Wilson et al. Ann. Emer. Med. 33(5), 495, 1999).In some embodiments, the abiraterone prodrug formulation furthercomprises benzyl alcohol. In some embodiments, the cosolvent, ifpresent, can be included at a level (e.g., about 0-50% of the solvent,such as about 10%) such that it does not cause irritation (or onlyminimal or tolerable irritation) at the injection site.

In some embodiments, the abiraterone prodrug formulation can comprisebenzyl benzoate as a cosolvent, for example, about 0-50% of the solvent,typically 0-35% or 0-30%, or about 20%. In some embodiments, theabiraterone prodrug formulation can comprise a combination of benzylalcohol and benzyl benzoate as cosolvents. In some embodiments, thebenzyl alcohol can be present in an amount of about 0-20% (e.g., 0-15%or 0-10%, such as about 10%) of the solvent, and benzyl benzoate can bepresent in an amount of about 0-50% (e.g., 0-35% or 0-30%, such as about20%) of the solvent, wherein the balance of the solvent can be any oneor more of the pharmaceutically acceptable oil described herein, such ascorn oil, castor oil, sesame oil, peanut oil, cottonseed oil, and/orMiglyol 812, etc. As discussed in more detail in the Examples section,the inclusion of benzyl benzoate in various oil vehicles was found to beadvantageous in various aspects. See e.g., FIGS. 13A-13E and Tables2A-2D. For example, the combination of benzyl alcohol and benzylbenzoate were shown to achieve a lower viscosity and glide force, whencompared with using just benzyl alcohol or benzyl benzoate. Further, itwas unexpectedly found that a representative abiraterone prodrug(abiraterone decanoate) formulation comprising an oil (corn oil, 70%)and benzyl alcohol (10%) and benzyl benzoate (20%) achieved a muchhigher abiraterone plasma exposure in monkeys when compared with aformulation comprising the same oil vehicle without benzyl benzoate,i.e., corn oil, at 90%, and benzyl alcohol at 10%, which hassubstantially the same concentration of abiraterone decanoate, and dosedat the same amount.

While the oil vehicles described herein are typically used for theabiraterone prodrugs of the present disclosure, it is also contemplatedthat such oil vehicles can be used for formulating other activeingredients. In some embodiments, the present disclosure also providesan oil vehicle comprising benzyl alcohol in an amount of about 0-20%(e.g., 0-15% or 0-10%, such as about 10%) of the oil vehicle, and benzylbenzoate in an amount of about 0-50% (e.g., 0-35% or 0-30%, such asabout 20%) of the oil vehicle, wherein the balance of the oil vehiclecan be any one or more of the pharmaceutically acceptable oil describedherein, such as corn oil, castor oil, sesame oil, peanut oil, cottonseedoil, and/or Miglyol 812, etc.

The solubility of the abiraterone esters can be affected upon adding aco-solvent to the vegetable oil vehicle. In some embodiments, theabiraterone ester is completely dissolved in the composition, and inother embodiments the abiraterone ester is partly dispersed in thecomposition. In one embodiment, the abiraterone esters are fullydissolved in the vehicle.

The abiraterone prodrug formulations can also contain pharmaceuticallyacceptable preservatives, polymers, antioxidants, antimicrobials,chelating agents, and other excipients such as citric acid, dextrose,ascorbic acid, benzalkonium chloride, benzoic acid, sodium betadexsulfobutyl ether, calcium chloride, sodium carbomethoxycellulose,chlorobutanol, creatine, croscarmellose, dibasic potassium phosphate,sodium docusate, sodium edetate, glycerin, sodium hyaluronate,hydroxypropyl betadex, lactic acid, lactose, lecithin, maleic acid,mannitol, meglumine, methylcellulose, methylparaben, microcrystallinecellulose, miripitium chloride, momothioglycerol, phenol, poloxamer 188,polyglactin, polysorbate 20, polysorbate 40, polysorbate 80,propylparaben, sodium acetate, sodium benzoate, sodium citrate, sorbitanmonolaurate, sorbitol, sucrose, tartaric acid, trisodium citrate,tromantadine, tromethamine, and urea.

The abiraterone prodrug formulations can be sterilized by methods knownby persons skilled in the art (for example, gamma irradiation, micronfiltration, and autoclaving).

Lon-Actin Release of Abiraterone

The abiraterone prodrugs and abiraterone prodrug formulations (e.g.,those containing compounds of Formula I or II as described herein) ofthe present disclosure are typically formulated to provide a long-actingrelease of abiraterone to a subject in need thereof, such as thosehaving a sex hormone-dependent benign or malignant disorder, a syndromedue to androgen excess, and/or a syndrome due to glucocorticoid excesssuch as hypercortisolemia, preferably as a parenteral formulation suchas intramuscular, intradermal, or subcutaneous formulation. In someembodiments, the abiraterone prodrugs and abiraterone prodrugformulations (e.g., those containing compounds of Formula I or II asdescribed herein) of the present disclosure can be formulated to delivertherapeutic blood plasma levels of abiraterone over an extended periodof time (e.g., at least 1 week, e.g., at least two weeks, at least 3weeks, at least 4 weeks, and up to six or eight weeks or more, etc.) tosubjects having a hormone-dependent benign or malignant disorder, asyndrome due to androgen excess, and/or a syndrome due to glucocorticoidexcess such as hypercortisolemia, following a single administration. Insome embodiments, the therapeutic blood plasma concentration ofabiraterone can be a concentration of at least 1 ng/ml, e.g., at least 2ng/ml, at least 4 ng/ml, at least 8 ng/ml. In some embodiments, thetherapeutic blood plasma concentration of abiraterone can also be about0.5 ng/ml or higher.

As shown herein, abiraterone acetate vegetable oil IM injections wereevaluated in dogs. Abiraterone acetate solutions in castor oil and theco-solvents benzyl alcohol and benzyl benzoate were prepared at variousstrengths (66-124 mg/ml) and injected intramuscularly into dogs, and theparent abiraterone drug blood plasma levels were measured over threeweeks (see FIG. 2). The data from the dog study indicate thatabiraterone acetate given as a solution in castor oil (with or withoutbenzyl alcohol) produced measurable blood levels out to 504 hours. Theabsolute bioavailabilities for these formulations were found to rangebetween 61.7 and 86.2%. This represents the first showing that it ispossible to deliver abiraterone to a subject for a prolonged period oftime with a single injection, which therefore allows a less frequentdosing, such as once a week or once in more than a week, e.g., thedosing frequency ranges from once a week to once every few months, suchas from once a week to once every eight weeks or from once a week toonce every three months.

Without wishing to be bound by theories, it is believed that theduration of action of the prodrug is dependent on the selection of theprodrug (e.g., the ester moiety) and the selection of the oil vehiclesince it is controlled by both the release rate of the prodrug from theoil vehicle into the aqueous tissue and the bioconversion rate of theester prodrug to the parent drug abiraterone. Unlike the case whereabiraterone acetate is dosed orally and the bioconversion occurs priorto the drug being absorbed (and thus the prodrug is not observed inblood plasma), when abiraterone prodrug is dosed parenterally in dogs(either IV or IM) the prodrug is observed in blood plasma (see e.g.,FIGS. 3-10) where it is converted into parent drug abiraterone.Therefore, an aspect of this disclosure is the selection of the esterprodrug and the vegetable oil/co-solvent vehicle so as to allow adequatesolubility of the ester prodrug in the vehicle to allow injection,controlled release of the ester prodrug from the oil depot (dependent onthe partition coefficient of the drug between oil and aqueous phases),and then bioconversion of the ester prodrug to the abiraterone parentdrug. A selection of abiraterone pro-drugs were prepared (acetate,propionate, butanoate, pentanoate, hexanoate, heptanoate, isocaproate,cypionate, and decanoate) and their solubilities in several vegetableoils and co-solvents determined (see Table 2).

Unit Dosage Forms

In some embodiments, the abiraterone prodrugs and abiraterone prodrugformulations (e.g., those containing compounds of Formula I or II asdescribed herein) of the present disclosure can be formulated as a unitdosage form. In some embodiments, the unit dosage form can include asufficient amount of the respective prodrug such that after a singleadministration (e.g., intramuscular injection) to a subject, e.g., asubject having a sex hormone-dependent benign or malignant disorder(e.g., metastatic castration resistant prostate cancer or metastaticcastration sensitive prostate cancer), a syndrome due to androgenexcess, and/or a syndrome due to glucocorticoid excess such ashypercortisolemia, the unit dosage form provides a therapeuticallyeffective blood plasma concentration of abiraterone in the subject for aperiod of at least two weeks, such as at least 3 weeks, at least 4weeks, at least 5 weeks, and up to six or eight weeks or more, etc. Insome embodiments, the therapeutic blood plasma concentration ofabiraterone can be a concentration of at least 1 ng/ml, e.g., at least 2ng/ml, at least 4 ng/ml, at least 8 ng/ml. In some embodiments, thetherapeutic blood plasma concentration of abiraterone can also be about0.5 ng/ml or higher. In some embodiments, the unit dosage form is aparenteral formulation such as intramuscular, intradermal, orsubcutaneous formulation. In some embodiments, the unit dosage form is anon-aqueous solution or suspension. In some embodiments, the unit dosageform comprises the abiraterone prodrug (e.g., compound of Formula I orII) dissolved or suspended in a pharmaceutically acceptable oil, e.g., avegetable oil such as castor oil, corn oil, sesame oil, cottonseed oil,peanut oil, poppy seed oil, tea seed oil, or soybean oil. In someembodiments, two or more different pharmaceutically acceptable oil canbe used in the unit dosage forms. In some embodiments, the unit dosageform can further comprise a pharmaceutically acceptable solvent, e.g.,an alcohol, an ester, and/or an acid, such as benzyl alcohol, benzylbenzoate, or a combination thereof. Other suitable ingredients for theunit dosage forms include those described herein.

The abiraterone prodrug (e.g., compound of Formula I or II) is typicallypresent in the unit dosage form at a concentration of about 25 mg/ml toabout 500 mg/ml (e.g., about 25 mg/ml, about 50 mg/ml, about 100 mg/ml,about 150 mg/ml, about 200 mg/ml, about 250 mg/ml, about 300 mg/ml,about 400 mg/ml, about 500 mg/ml, or any range between the recitedvalues). The amount of abiraterone prodrug in the unit dosage forms canvary, depending on various factors such as the clearance rate of therespective abiraterone prodrug, the intended dosing frequency and thedesired plasma levels, etc. Typically, the amount of the abirateroneprodrug can be in the range of about 50 mg to about 2000 mg, which ifexpressed as equivalent of abiraterone, can typically range from about25 mg to about 1750 mg. In some embodiments, to achieve a less frequentdosing frequency, such as a once a month dosing frequency, the prodrugcan be included in the unit dosage form at a concentration as high assafely tolerable to a subject user. Typically, the unit dosage form isformulated to have a viscosity suitable for parenteral injection, suchas suitable for intramuscular, intradermal, or subcutaneous injection.

In some embodiments, the unit dosage form can be formulated to achievecertain pharmacokinetic (PK) profiles, e.g., a PK profile with asubstantially flat curve after an initial rising period. Typically,after the unit dosage form is administered to a subject, during theinitial few hours and up to a few days (e.g., 5 days or a week) postadministration, the plasma concentration of abiraterone in the subjectcan be increased, which is then gradually plateaued, see e.g., FIGS.2-4. In some embodiments, after this initial rising period, the plasmaconcentration of abiraterone in the subject can be plateaued and can besubstantially constant for an extended period of time, for example, forat least a few days (e.g., 2, 3, 4, 5, or 6 days), or for at least 1week, at least 2 weeks, etc.

In some embodiments, the unit dosage form is suitable for once a month(or once in more than a month) dosing, and upon a single administration(e.g., intramuscularly) to a subject in need thereof, the unit dosageform achieves a PK profile characterized by one or more of thefollowing: (a) the unit dosage form provides a therapeutically effectiveblood plasma concentration of abiraterone in the subject for at least 4weeks; (b) a single dose C_(max) of abiraterone of between about 10ng/ml and about 400 ng/ml (e.g., between about 50 ng/ml and about 100ng/ml, or between about 15 ng/ml and about 160 ng/ml); (c) no foodeffect; (d) a single dose C_(max) of abiraterone reduced by at least 30%compared to the C_(max) of abiraterone observed at steady state for aonce daily oral dose of Zytiga® at 1000 mg without food; (e) a singledose C_(min) of abiraterone at day 28 post administration between about1 ng/ml and about 8 ng/ml, or above about 8 ng/ml; (f) the blood plasmaconcentration of abiraterone remains substantially constant, e.g., forat least 1 week, e.g., between 1 week and 3 weeks post administration.In some embodiments, substantially constant for a period of time canmean that the highest concentration observed for any day (i.e., 24hours) during that time period is no greater than 4 fold, for example,no greater than 2 fold, of the lowest concentration observed for thesame day. No food effect should be generally understood as that nosignificant differences in PK are observed when the unit dosage form isadministered to subjects with food or without food, for example, in someembodiments, no food effect can mean that the C_(max) and AUC ofabiraterone are substantially the same (e.g., between 80% to 125%)between subjects dosed at a fed state or fasted state. A single doseC_(max) as used herein should be understood as the C_(max) achievedfollowing a single administration to a treatment naïve subject(generally refers to a subject who has not received any abirateronemedication within at least 3 days, such as at least 1 week, prior to theadministration and with no observable plasma abiraterone prior to theadministration). A single dose C_(min) used herein refers to the minimumconcentration observed for a given day following a single administrationto a treatment naïve subject, e.g., at day 28 post administration.

In some embodiments, the unit dosage form is suitable for once a month(or once in more than a month) dosing, and upon administration (e.g.,intramuscularly) of the unit dosage form once in a month to a subject inneed thereof, the unit dosage form achieves (a) a steady state C_(max)of abiraterone of between about 10 ng/ml and about 400 ng/ml (e.g.,between about 50 ng/ml and about 100 ng/ml, or between about 15 ng/mland about 160 ng/ml); (b) no food effect; (c) a steady state C_(max) ofabiraterone reduced by at least 30% compared to the C_(max) ofabiraterone observed at steady state for a once daily oral dose ofZytiga® at 1000 mg without food; (d) a steady state C_(min) ofabiraterone between about 1 ng/ml and about 8 ng/ml, or above about 8ng/ml; and (g) the blood plasma concentration of abiraterone remainssubstantially constant, e.g., for at least 1 week, e.g., between 1 weekand 3 weeks post each administration. A steady state C_(max) or C_(min)as used herein should be understood as the C_(max) or C_(min) observedafter a steady state is reached, typically following severaladministrations to a subject.

In some embodiments, the unit dosage form can be packaged in a containersuch as a vial or ampule. In some embodiments, the unit dosage form canbe included in a pre-filled syringe or in a kit with a syringe, such asa disposable syringe. Other packaging and/or containers are also useful,which are known to those skilled in the art. In some embodiments, a kitcomprising multiple unit dosage forms described herein is also provided.In some embodiments, the kit can further comprise a syringe. While insome embodiments, it is advantageous to prepare the abiraterone prodrugformulations in unit dosage forms, in some embodiments, the presentdisclosure also provides abiraterone prodrug formulations that allowmultiple single uses, or abiraterone prodrug formulations that can besubdivided into multiple unit dosage forms.

Exemplary Specific Formulations

In some embodiments, the present disclosure also provides some specificabiraterone prodrug formulations, which can in some embodiments be in aunit dosage form or a multiple unit dosage form. For example, the tablesbelow (Table A and B) show some representative abiraterone ester prodrugformulation in an oil vehicle. All numeric values in the tables shouldbe understood as preceded by the term “about.” The concentration ofabiraterone prodrug refers to the amount of abiraterone prodrug in mgper ml of the final formulation, which can be a solution or suspension.The amount of oil (the primary solvent) and co-solvent in the tables isexpressed as volume percentage of solvent, which includes both the oiland co-solvent. Suitable oil include any of the pharmaceuticallyacceptable oil as described herein. Suitable co-solvents also includeany of those described herein, e.g., an alcohol, an ester, and/or anacid, such as benzyl alcohol, benzyl benzoate, or a combination thereof,see e.g., Table B. One example of suitable co-solvents is benzylalcohol. One example of suitable co-solvents is a combination of benzylalcohol and benzyl benzoate. In some embodiments, no co-solvent isincluded in the formulation. In some embodiments, the co-solvent doesnot include benzyl benzoate. Other optionally ingredients are describedherein.

TABLE A Exemplary Formulations Amount/Concentration Exemplary MoreExemplary Ingredients Typical range Range Abiraterone prodrug 25 mg/ml50 mg/ml to 75 mg/ml to 300 (e.g., abiraterone to 500 300 mg/ml; mg/mlacetate, abiraterone mg/ml 100 mg/ml to decanoate, abiraterone 300 mg/mlpentanoate, abiraterone hexanoate, abiraterone heptanoate, abirateroneisocaproate, or abiraterone cypionate) Oil (e.g., castor oil, 50% to 70%to 100% 80% to 100% of corn oil) 100% of of solvent solvent, such assolvent 90% Co-solvent (e.g., benzyl 0% to 50% 0% to 40% 0% to 30% or 0%alcohol, benzyl of solvent or 0% to 30% to 20% of solvent, benzoate, orof solvent such as 10%, combination thereof) or 30% Other optionalingredients

As shown in FIGS. 13A-13E and the Examples section, benzyl alcoholand/or benzyl benzoate can enhance solubilities of abiraterone prodrugsof the present disclosure in oil vehicles, such as corn oil, and canlower viscosities and glide force of various oil vehicles, includingcorn oil, sesame oil, peanut oil, cottonseed oil, and Miglyol 812 (amixture of medium chain triglycerides, mainly caprylic/caprictriglycerides). In some embodiments, the present disclosure provides anabiraterone prodrug formulation comprising the abiraterone prodrug and apharmaceutically acceptable carrier, wherein the pharmaceuticallyacceptable carrier comprises a pharmaceutically acceptable oil (e.g.,described herein), benzyl alcohol, and benzyl benzoate. In someembodiments, the abiraterone prodrug can be abiraterone decanoate. Insome embodiments, the abiraterone prodrug can be abirateroneisocaproate. The pharmaceutically acceptable oil typically comprises atriglyceride derived from fatty acids. In some embodiments, thepharmaceutically acceptable oil can be nature oil, synthetic oil, orsemi-synthetic oil, such as fractionated coconut oil and medium-chaintriglycerides, such as those sold under the trademark Miglyol. In someembodiments, the pharmaceutically acceptable oil can be selected fromvegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanutoil (arachis oil), poppy seed oil, tea seed oil, and soybean oil. Insome embodiments, the present disclosure provides certain exemplaryformulations shown in Table B.

TABLE B Further Exemplary Formulations Amount/Concentration MoreExemplary Ingredients Typical Exemplary range Range Abiraterone prodrug25 mg/ml to 500 50 mg/ml to 300 75 mg/ml to 300 (e.g., abiraterone mg/mlmg/ml; 100 mg/ml to mg/ml, such as 150 decanoate or 300 mg/ml mg/ml toabout 250 abiraterone mg/ml isocaproate) Oil (e.g., corn oil, 30% to100% of 50% to 90% of solvent 60% to 90% of sesame oil, peanut oil,solvent solvent, such as 70% cottonseed oil, and/or Miglyol 812)Co-solvent 1 (e.g., 0% to 20% of solvent 0% to 15% of solvent 0% to 10%of solvent, benzyl alcohol) such as 10% benzyl benzoate 0% to 50% ofsolvent 0% to 35% of solvent 0% to 30% of solvent, such as 20% Otheroptional ingredients

In some embodiments, the present disclosure also provides the followingspecific formulations: abiraterone acetate solution in Castor oil with aconcentration of about 50 mg/mL to about 200 mg/mL (such as 70 mg/mL);abiraterone acetate solution in 10% Benzyl alcohol/90% Castor oil with aconcentration of about 50 mg/mL to about 200 mg/mL (such as about 90mg/mL); abiraterone acetate solution in 50% Benzyl benzoate/50% Castoroil with a concentration of about 50 mg/mL to about 200 mg/mL (such asabout 125 mg/mL); abiraterone propionate solution in 10% Benzylalcohol/90% Castor oil with a concentration of about 50 mg/mL to about300 mg/mL (such as about 200 mg/mL); abiraterone propionate solution in10% Benzyl alcohol/90% Corn oil with a concentration of about 50 mg/mLto about 300 mg/mL (such as about 168 mg/mL); abiraterone decanoatesolution in Castor oil with a concentration of about 100 mg/mL to about300 mg/mL (such as 160 mg/mL or 170 mg/mL); abiraterone decanoatesolution in Corn oil with a concentration of about 100 mg/mL to about300 mg/mL (such as 160 mg/mL or 170 mg/mL); abiraterone decanoatesolution in 10% Benzyl alcohol/90% Castor oil with a concentration ofabout 100 mg/mL to about 300 mg/mL (such as 160 mg/mL or 170 mg/mL);abiraterone decanoate solution in 10% Benzyl alcohol/90% Corn oil with aconcentration of about 100 mg/mL to about 300 mg/mL (such as 160 mg/mLor 170 mg/mL); abiraterone decanoate solution in 70% Corn Oil, 10%Benzyl Alcohol, 20% Benzyl Benzoate with a concentration of about 150mg/mL to about 300 mg/mL (such as about 200 mg/ml or about 240 mg/ml);abiraterone isocaproate 90% in Corn Oil, 10% Benzyl Alcohol Solutionwith a concentration of about 120 mg/mL to about 200 mg/mL (such asabout 150 mg/ml or about 160 mg/ml). In some embodiments, the presentdisclosure also provides any of the specific formulations preparedherein such as in Examples 3A-3J. In some embodiments, the presentdisclosure also provides a formulation described herein in Example 1.

Method of Treatment

Some embodiments of the present disclosure are directed to methods ofdelivering abiraterone to a subject in need thereof. In variousembodiments, the present disclosure also provides methods of treating orprevent diseases or disorders for which administering abiraterone isbeneficial.

In some embodiments, the present disclosure provides a method ofdelivering abiraterone to a subject in need thereof, the methodcomprising administering to the subject any of the abiraterone prodrugsor abiraterone prodrug formulations of the present disclosure. In someembodiments, the subject suffers from a sex hormone-dependent benign ormalignant disorder, e.g., an androgen-dependent or an estrogen-dependentdisorder as described herein. In some embodiments, the subject suffersfrom a syndrome due to androgen excess and/or a syndrome due toglucocorticoid excess such as hypercortisolemia, e.g., as describedherein. In any of the embodiments described herein, unless directlycontradictory, the subject can be a human subject, e.g., a human patienthaving a hormone-dependent benign or malignant disorder, a syndrome dueto androgen excess, and/or a syndrome due to glucocorticoid excess suchas hypercortisolemia, e.g., as described herein. Hormone-dependentbenign or malignant disorder as used herein, whether preceded with theterm “sex” should be understood as sex hormone-dependent benign ormalignant disorder, such as androgen-dependent or estrogen-dependentdisorders.

As detailed herein, in a monkey PK study, it was shown that a singleintramuscular injection of a representative abiraterone prodrug,abiraterone decanoate, can achieve a prolonged CYP17A1 inhibition, withsustained increase of progesterone level and reduction of cortisol andtestosterone level up to eight weeks. As shown in FIG. 14D, it isexpected that inhibition of CYP17A1 17α-hydroxylase and C17,20-lyaseactivities will lead to (1) increases in levels of progesterone and themineralocorticoids; (2) reductions in levels of glucocorticoids such ascortisol; and (3) reductions in levels of sex hormones, e.g., androgenssuch as testosterone and dihydrotestosterone, and estrogens such asestradiol. Thus, the abiraterone prodrugs and prodrug formulations ofthe present disclosure can be advantageously used for inhibiting CYP17A1activity, reducing glucocorticoids levels, such as cortisol levels,reducing sex hormone levels such as androgen and/or estrogen levels,and/or treating disorders associated with high glucocorticoids levels,such as cortisol levels, and/or treating disorders due to high sexhormone levels such as androgen and/or estrogen levels.

In some embodiments, the present disclosure provides a method ofinhibiting CYP17A1 activity such as inhibiting 17α-hydroxylase activityand 17,20-lyase activity, the method comprising administering to thesubject any of the abiraterone prodrugs or abiraterone prodrugformulations of the present disclosure. In some embodiments, the subjectsuffers from a sex hormone-dependent benign or malignant disorder, e.g.,as described herein. In some embodiments, the subject suffers from asyndrome due to androgen excess and/or a syndrome due to glucocorticoidexcess such as hypercortisolemia, e.g., as described herein.

In some embodiments, the present disclosure provides a method ofreducing the level of glucocorticoids (e.g., cortisol) in a subject inneed thereof, the method comprising administering to the subject any ofthe abiraterone prodrugs or abiraterone prodrug formulations of thepresent disclosure. In some embodiments, the subject suffers from asyndrome due to glucocorticoid excess such as hypercortisolemia asdescribed herein, such as Cushing's syndrome or Cushing's disease.

In some embodiments, the present disclosure provides a method ofreducing the level of androgens (e.g., testosterone and/ordihydrotestosterone) and/or estrogens in a subject in need thereof, themethod comprising administering to the subject any of the abirateroneprodrugs or abiraterone prodrug formulations of the present disclosure.In some embodiments, the subject suffers from a syndrome due to androgenexcess, such as congenital adrenal hyperplasia (e.g., classical ornonclassical congenital adrenal hyperplasia), endometriosis, polycysticovary syndrome precocious puberty, hirsutism, etc. In some embodiments,the subject suffers from an androgen and/or estrogen associated cancer,such as prostate cancer or breast cancer.

In some embodiments, a method of treating a sex hormone-dependent benignor malignant disorder, a syndrome due to androgen excess and/or asyndrome due to glucocorticoid excess such as hypercortisolemia isprovided. Typically, the method comprises administering to a subject inneed thereof a therapeutically effective amount of any of theabiraterone prodrugs or abiraterone prodrug formulations of the presentdisclosure. In any of the embodiments described herein, unless directlycontradictory, the subject can be a human subject, e.g., a human patienthaving a hormone-dependent benign or malignant disorder, a syndrome dueto androgen excess and/or a syndrome due to glucocorticoid excess suchas hypercortisolemia, e.g., as described herein.

The administering in the methods herein is not limited to any particularroute. However, in some preferred embodiments, the administering can bea parenteral administration, such as an intramuscular injection,intradermal injection, or subcutaneous injection. Parenteraladministration can in some embodiments be advantageous. For example, insome embodiments, the administering can be a parenteral administration,such as an intramuscular injection, which can be carried out withoutregard to whether the subject has food. In other words, the fed orfasted status of the subject is not important. This removes therestriction associated with the currently marketed Zytiga® formulation,which states that the medication “must be taken on an empty stomach withwater at least 1 hour before or 2 hours after a meal.” Therefore, amongother advantages, the methods herein can improve patient compliance.

Various sex hormone-dependent benign or malignant disorders can betreated with the methods herein. In some embodiments, thehormone-dependent benign or malignant disorders can beandrogen-dependent disorders and estrogen-dependent disorders such asandrogen or estrogen-dependent cancers. In some embodiments, the sexhormone-dependent benign or malignant disorder can be prostate cancer orbreast cancer. In some embodiments, the sex hormone-dependent benign ormalignant disorder is castration resistant prostate cancer or castrationsensitive prostate cancer. In some embodiments, the sexhormone-dependent benign or malignant disorder can be metastaticcastration resistant prostate cancer or metastatic castration sensitiveprostate cancer. In some embodiments, the sex hormone-dependent benignor malignant disorder can also be ovarian cancer, bladder cancer,hepatocellular carcinoma, or lung cancer. Various non-oncologicsyndromes due to androgen excess and/or due to glucocorticoid excesssuch as hypercortisolemia can also be treated with the methods herein,for example, syndromes due to androgen excess such as endometriosis,polycystic ovary syndrome, classical or nonclassical congenital adrenalhyperplasia, precocious puberty, hirsutism, etc., and/or syndromes dueto cortisole excess such as Cushing's syndrome, Cushing's disease, etc.

The methods herein can be used in conjunction with one or moreadditional therapies for the respective disease or disorder. Forexample, the Zytiga® label (abiraterone acetate) states that patientsreceiving Zytiga® should also receive a gonadotropin-releasing hormone(GnRH) analog concurrently or should have had bilateral orchiectomy.Accordingly, in some embodiments of methods of the present disclosure,the subject can also be treated with a gonadotropin-releasing hormoneanalog and/or bilateral orchiectomy. In some embodiments, the methodalso comprises administering to the subject an effective amount ofprednisone or prednisolone, either concurrently or sequentially.However, in some embodiments, the methods herein can also achieve thedesired therapeutic effect without causing adrenocortical insufficiency,which thus can avoid co-administering prednisone or prednisolone. Insome embodiments, the subject is not treated with agonadotropin-releasing hormone analog and/or bilateral orchiectomy. Insome embodiments, the subject is not administered with prednisone orprednisolone.

In some embodiments, the method can comprise administering one or moreother drug or agent (for example, another cancer chemotherapeutic drug,hormone replacement drug, or hormone ablation drug) to the subject,either concurrently or sequentially, through the same route or adifferent route of administration. In some embodiments, the other drugor agent can be a steroid, such as prednisone, prednisolone, and/ormethylprednisolone. In some embodiments, the other drug or agent can bea chemotherapy drug, such as paclitaxel, mitoxantrone, and/or docetaxel.In some embodiments, the other agent or drug can be a GnRH agonist, suchas Leuprolide, deslorelin, goserelin, or triptorelin, e.g., leuprolideacetate (e.g., a long acting IM injectable formulation). In someembodiments, the other agent or drug can be seocalcitol, bicalutamide,flutamide, a glucocorticoid including, but not limited to,hydrocortisone, prednisone, prednisolone, or dexamethasone. The amountof the other drugs or agents to be administered can vary, typically canbe an amount that is effective in treating the respective disease ordisorder (e.g., prostate cancer) either alone or in combination with theabiraterone prodrug or abiraterone prodrug formulation of the presentdisclosure.

Additional suitable other drugs or agents include those describedherein. For example, useful other drugs or agents include, but are notlimited to, anticancer agents, hormone ablation agents, anti-androgenagents, differentiating agents, anti-neoplastic agents, kinaseinhibitors, anti-metabolite agents, alkylating agents, antibioticagents, immunological agents, interferon-type agents, intercalatingagents, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, mitoticinhibitors, matrix metalloprotease inhibitors, genetic therapeutics, andanti-androgens.

For example, suitable anti-cancer agents, including but not limited to,acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin,altretamine, amifostine, amsacrine, anagrelide, anastrozole, ancestim,bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix,cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol,doxifluridine, bromocriptine, carmustine, cytarabine, diclofenac,edelfosine, edrecolomab, eflornithine, emitefur, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, glycopine, heptaplatin,ibandronic acid, imiquimod, iobenguane, irinotecan, irsogladine,lanreotide, leflunomide, lenograstim, lentinan sulfate, letrozole,liarozole, lobaplatin, lonidamine, masoprocol, melarsoprol,metoclopramide, mifepristone, miltefosine, mirimostim, mitoguazone,mitolactol, molgramostim, nafarelin, nartograstim, nedaplatin,nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin, pamidronicacid, pegaspargase, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, porfimer sodium, raloxifene, raltitrexed, rasburicase,rituximab, romurtide, sargramostim, sizofiran, sobuzoxane, sonermin,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin,trilostane, trimetrexate, ubenimex, valrubicin, verteporfin,vinorelbine. Suitable anti-androgen agents include but are not limitedto bicalutamide, flutamide and nilutamide. Suitable differentiatingagents include, but are not limited to, polyamine inhibitors; vitamin Dand its analogs, such as, calcitriol, doxercalciferol and seocalcitol;metabolites of vitamin A, such as, ATRA, retinoic acid, retinoids;short-chain fatty acids; phenylbutyrate; and nonsteroidalanti-inflammatory agents. anti-neoplastic agent, including, but notlimited to, tubulin interacting agents, topoisomerase inhibitors andagents, acitretin, alstonine, amonafide, amphethinile, amsacrine,ankinomycin, anti-neoplaston, aphidicolin glycinate, asparaginase,baccharin, batracylin, benfluron, benzotript, bromofosfamide,caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone,clanfenur, claviridenone, crisnatol, curaderm, cytarabine, cytocytin,dacarbazine, datelliptinium, dihaematoporphyrin ether, dihydrolenperone,dinaline, distamycin, docetaxel, elliprabin, elliptinium acetate,epothilones, ergotamine, etoposide, etretinate, fenretinide, galliumnitrate, genkwadaphnin, hexadecylphosphocholine, homoharringtonine,hydroxyurea, ilmofosine, isoglutamine, isotretinoin, leukoregulin,lonidamine, merbarone, merocyanlne derivatives, methylanilinoacridine,minactivin, mitonafide, mitoquidone, mitoxantrone, mopidamol,motretinide, N-(retinoyl)amino acids, N-acylated-dehydroalanines,nafazatrom, nocodazole derivative, ocreotide, oquizanocinc, paclitaxel,pancratistatin, pazelliptine, piroxantrone, polyhaematoporphyrin,polypreic acid, probimane, procarbazine, proglumide, razoxane,retelliptine, spatol, spirocyclopropane derivatives, spirogermanium,strypoldinone, superoxide dismutase, teniposide, thaliblastine,tocotrienol, topotecan, ukrain, vinblastine sulfate, vincristine,vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, andwithanolides. a kinase inhibitor including p38 inhibitors and CDKinhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP),COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib,and etoricoxib, SOD mimics or α_(v)β₃ inhibitors. Suitableanti-metabolite agents may be selected from, but not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, cyclopentyl cytosine, cytarabine phosphate stearate,cytarabine conjugates, dezaguanine, dideoxycytidine, dideoxyguanosine,didox, doxifluridine, fazarabine, floxuridine, fludarabine phosphate,5-fluorouracil, N-(2′-furanidyl)-5-fluorouracil, isopropyl pyrrolizine,methobenzaprim, methotrexate, norspermidine, pentostatin, piritrexim,plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinaseinhibitors, and uricytin. Suitable alkylating agents may be selectedfrom, but not limited to, aldo-phosphamide analogues, altretamine,anaxirone, bestrabucil, budotitane, carboplatin, carmustine,chlorambucil, cisplatin, cyclophosphamide, cyplatate,diphenylspiromustine, diplatinum cytostatic, elmustine, estramustinephosphate sodium, fotemustine, hepsul-fam, ifosfamide, iproplatin,lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine,ranimustine, semustine, spiromustine, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol. Suitable antibiotic agents maybe selected from, but not limited to, aclarubicin, actinomycin D,actinoplanone, adriamycin, aeroplysinin derivative, amrubicin,anthracycline, azino-mycin-A, bisucaberin, bleomycin sulfate,bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin,ditrisarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen,elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1,esperamicin-A1b, fostriecin, glidobactin, gregatin-A, grincamycin,herbimycin, corticosteroids such as hydrocortisone, idarubicin,illudins, kazusamycin, kesarirhodins, menogaril, mitomycin, neoenactin,oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin,prednisone, prednisolone, pyrindanycin A, rapamycin, rhizoxin,rodorubicin, sibanomicin, siwenmycin, sorangicin-A, sparsomycin,talisomycin, terpentecin, thrazine, tricrozarin A, and zorubicin.Non-limiting examples of suitable steroids include hydrocortisone,prednisone, prednisolone, or dexamethasone.

Dosing Regimen

The abiraterone prodrugs and formulations of the present disclosure cangenerally provide a long-acting release of abiraterone to a subjectuser. This long-acting release profile allows administering abirateroneto a subject user at a low dosing frequency, such as once a week or evenless frequently, which can improve patient compliance and reduce pillburdens.

In some embodiments, the methods herein can have a dosing regimen ofonce a week or once in more than a week. Typically, the dosing frequencycan range from once a week to once every few months, such as from once aweek to once every eight weeks, or from once a week to once every threemonths. In some embodiments, the dosing amount for each dose is about 50mg to about 2000 mg (e.g., about 500 mg, about 1000 mg, about 1500 mg,or any ranges between the recited values) of abiraterone prodrug. Insome embodiments, the dosing amount of abiraterone prodrug for each doseis about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg, about 1mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg,about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any ranges betweenthe recited values) of body weight of a subject. In some embodiments,the methods herein can comprise administering to the subject in needthereof an abiraterone prodrug or abiraterone prodrug formulation of thepresent disclosure, once a week, or once in more than a week, such asonce in two weeks, once in a month, wherein the administering provides atherapeutically effective plasma concentration (e.g., as describedherein, such as 0.5 ng/ml and above, 1 ng/ml and above, 8 ng/ml andabove, or 8.4 ng/ml and above) of abiraterone in the subject for aprolong period of time, such as more than 1 week, more than 2 weeks,more than 3 weeks, more than 4 weeks, and up to six or eight weeks ormore, etc. In some embodiments, the administering can provide a singledose C_(max) of abiraterone between about 10 ng/ml and about 400 ng/ml(e.g., between about 50 ng/ml and about 100 ng/ml, or between about 15ng/ml and about 160 ng/ml). In some embodiments, the administering canprovide a steady state C_(max) of abiraterone between about 10 ng/ml andabout 400 ng/ml (e.g., between about 50 ng/ml and about 100 ng/ml, orbetween about 15 ng/ml and about 160 ng/ml). In some embodiments, theadministering can provide a single dose C_(min) of abiraterone betweenabout 1 ng/ml and about 8 ng/ml, or above about 8 ng/ml such as above8.4 ng/ml, at each day from day 1 to day 7, or day 1 to day 14, or day 1to day 21, or day 1 to day 28 post administration. In some embodiments,the administering can provide a steady state C_(min) of abirateronebetween about 1 ng/ml and about 8 ng/ml, or above about 8 ng/ml such asabove 8.4 ng/ml.

Abiraterone prodrugs suitable for use for a once a week or once in morethan a week dosing methods above include those described herein. In someembodiments, the abiraterone prodrug can be a lipophilic ester ofabiraterone described herein, for example, an acetate, a propionate, abutanoate, a (vaterate) pentanoate, an isocaproate, a buciclate, acyclohexanecarboxylate, a phenyl propionate, caproate (hexanoate), aenanthate (heptanoate), a cypionate, an octanoate, a noncanoate, adecanoate, an undecanoate, a dodecanoate, a tridecanoate, atetradecanoate, a pentadecanoates, and a hexadecanoate. In somepreferred embodiments, the abiraterone prodrug can be a compound ofFormula I, for example, a compound of Formula I, wherein R¹ is a C₇₋₁₆alkyl, e.g., an alkyl having a formula of —(CH₂)_(n)—CH₃, wherein n isan integer between 6 and 12 (e.g., n is 6, 7, 8, 9, 10); or R¹ isrepresented by the formula —(CH₂)_(n)-Cy, wherein n is an integer of1-6, and Cy is a C₃₋₆ cycloalkyl or phenyl, for example, in morespecific embodiments, n can be 1 or 2, and Cy is cyclopentyl,cyclohexyl, or phenyl; or R¹ is

or R¹ is

or

In some embodiments, the abiraterone prodrug can be a compound ofFormula II, wherein R² in Formula II can be a C₁₋₁₆ alkyl, e.g., analkyl having a formula of —(CH₂)_(n)—CH₃, wherein n is an integerbetween 0 and 12; or R² in Formula II can be represented by the formula—(CH₂)_(n)-Cy, wherein n is an integer of 1-6, and Cy is a C₃₋₆cycloalkyl or phenyl, for example, in more specific embodiments, n canbe 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl; or R² inFormula II can be

or

In some embodiments, the abiraterone prodrug can also be abirateroneacetate or any of the Examples 2A-2H. In some embodiments, theabiraterone prodrug can be abiraterone acetate, abiraterone propionate,or abiraterone decanoate. In some specific embodiments, the abirateroneester can be abiraterone pentanoate, abiraterone hexanoate, abirateroneheptanoate, abiraterone decanoate, abiraterone isocaproate, orabiraterone cypionate. In any of the embodiments described herein,unless otherwise specified or directly contradictory from context, theabiraterone prodrug can be abiraterone decanoate.

In some embodiments, a once a month or once in more than a month dosingis desired, e.g., the dosing frequency ranges from once a month to onceevery few months, such as from once a month to once every two months, orfrom once a month to once every three months. In such embodiments, theabiraterone prodrug needs to not only release abiraterone slowly butalso to release abiraterone in a sufficient plasma concentration suchthat it can be beneficial to the subject user. The once a month or oncein more than a month dosing is typically a parenteral administration,such as intramuscularly, intradermally, or subcutaneously. In any of theembodiments herein, unless directly contradictory, the administrationcan be an intramuscular administration.

As detailed herein, a single intramuscular administration of abirateroneacetate was found to provide extended release of abiraterone. However,the dog PK study shows that similar administration of abirateronepropionate did not improve the extend release of abiraterone acetate,and in fact, the abiraterone release observed from the propionate wasbelow that observed for the acetate at all time points measured.Further, it was also unexpectedly found that elongation of the alkylchain to abiraterone butanoate led to a sharp reduction of solubility invarious oil vehicle. Despite of this unexpected trend, the presentinventors found that certain abiraterone prodrugs or abiraterone prodrugformulations of the present disclosure, for example, compounds ofFormula I, such as abiraterone decanoate, can be superior for use in aonce a month or once in more than a month dosing than the acetate,propionate, or butanoate. It was also found that the PK profile, such ast_(1/2), of certain abiraterone prodrugs or abiraterone prodrugformulations of the present disclosure, for example, compounds ofFormula I, such as abiraterone decanoate, does not vary significantlywhen a different oil vehicle is used. In contrast, as detailed inExample 5B, some variabilities of PK profiles for abiraterone propionatewere observed, depending on whether it was formulated in castor oil orcorn oil.

In some specific embodiments, the present disclosure provides a methodof treating a sex hormone-dependent benign or malignant disorder (e.g.,as described herein), a syndrome due to androgen excess, and/or asyndrome due to glucocorticoid excess such as hypercortisolemia, in asubject in need thereof, the method comprising parenterallyadministering to the subject a therapeutically effective amount of acompound of Formula I (e.g., described herein), or a pharmaceuticalcomposition comprising the compound of Formula I (e.g., describedherein), once a month or once in more than a month. In some embodiments,the parenterally administering is intramuscularly, intradermally, orsubcutaneously administering. In some preferred embodiments, in thecompound of Formula I, R¹ is a C₇₋₁₆ alkyl, e.g., an alkyl having aformula of —(CH₂)_(n)—CH₃, wherein n is an integer between 6 and 12(e.g., n is 6, 7, 8, 9, or 10); or R¹ is represented by the formula—(CH₂)_(n)-Cy, wherein n is an integer of 1-6, and Cy is a C₃₋₆cycloalkyl or phenyl, for example, in more specific embodiments, n canbe 1 or 2, and Cy is cyclopentyl, cyclohexyl, or phenyl; or R¹ is

or R¹ is

or

In some embodiments, the administering provides a therapeuticallyeffective blood plasma concentration of abiraterone in the subject for aperiod of at least 4 weeks, such as at least 5 weeks, and up to six oreight weeks or more, etc. In some embodiments, the therapeutic bloodplasma concentration of abiraterone can be a concentration of at least 1ng/ml, e.g., at least 2 ng/ml, at least 4 ng/ml, at least 8 ng/ml. Insome embodiments, the therapeutically effective blood plasmaconcentration of abiraterone can also be about 0.5 ng/ml or higher. Insome embodiments, the administering can provide a single dose C_(max) ofabiraterone between about 10 ng/ml and about 400 ng/ml (e.g., betweenabout 50 ng/ml and about 100 ng/ml, or about 15 ng/ml and about 160ng/ml). In some embodiments, the administering can provide a steadystate C_(max) of abiraterone between about 10 ng/ml and about 400 ng/ml(e.g., between about 50 ng/ml and about 100 ng/ml, or between about 15ng/ml and about 160 ng/ml). In some embodiments, the administering canprovide a single dose C_(min) of abiraterone at day 28 postadministration between about 1 ng/ml and about 8 ng/ml, or above about 8ng/ml, e.g., above about 8.4 ng/ml. In some embodiments, theadministering can provide a steady state C_(min) of abiraterone betweenabout 1 ng/ml and about 8 ng/ml, or above about 8 ng/ml, e.g., aboveabout 8.4 ng/ml. In some embodiments, the blood plasma concentration ofabiraterone in the subject can remain substantially constant, e.g., forat least 1 week, e.g., between 1 week and 3 weeks post administration.In some embodiments, the administering is carried out without regard towhether the subject has food. In some embodiments, the administeringprovides a single dose C_(max) of abiraterone reduced by at least 30%compared to the C_(max) of abiraterone observed at steady state for aonce daily oral dose of Zytiga® at 1000 mg without food. In someembodiments, the administering provides a steady state C_(max) ofabiraterone reduced by at least 30% compared to the C_(max) ofabiraterone observed at steady state for a once daily oral dose ofZytiga® at 1000 mg without food. In some embodiments, the pharmaceuticalcomposition comprising the compound of Formula I can be formulated as aunit dosage form described herein. Suitable carriers, oil vehicles,excipients for such pharmaceutical compositions include those describedherein.

The abiraterone prodrugs and abiraterone prodrug formulations of thepresent disclosure can be administered to a subject in need thereof asthe only source of abiraterone. However, in some embodiments, otherabiraterone medications/formulations are not excluded. For example, insome embodiments, the administering herein can be combined, eitherconcurrently or sequentially in any order, with an oral administrationof abiraterone acetate, such as the Zytiga® formulation. In someembodiments, the subject can use the abiraterone prodrugs andabiraterone prodrug formulations as a supplement to an existingabiraterone therapy. Moreover, the administering herein is not limitedto administering a single abiraterone prodrug or abiraterone prodrugformulation of the present disclosure. In some embodiments, two or moreabiraterone prodrugs and abiraterone prodrug formulations of the presentdisclosure can be administered to the subject.

In some embodiments, prior to a once a month or once in more than amonth dosing, the methods herein can include an initial treatment periodwith a higher dosing frequency, such as a once a week or once in twoweeks dosing. The initial treatment period can include administering thesame abiraterone prodrug or a different abiraterone medication such as adifferent abiraterone prodrug. Typically, the initial treatment periodcan be used to achieve a blood plasma concentration of abiraterone ofabout 1 ng/ml to about 8 ng/ml or above about 8 ng/ml, prior to the oncea month or once in more than a month dosing described herein. However,in some embodiments, the methods herein do not include such initialtreatment period.

As discussed herein, the abiraterone prodrugs and abiraterone prodrugformulations of the present disclosure have many advantages over thecurrently marketed Zytiga® product. For example, administering theabiraterone prodrugs and abiraterone prodrug formulations of the presentdisclosure to a subject typically results in reduced C_(max) ofabiraterone (e.g., reduced by at least 30% compared to the C_(max) ofabiraterone observed at steady state for a once daily oral dose ofZytiga® at 1000 mg without food).

Thus, in some embodiments, the present disclosure provides a method oftreating subjects having side effects related to high abirateroneexposure, such as having abiraterone C_(max) related side effects, themethod comprising administering abiraterone prodrugs and abirateroneprodrug formulations of the present disclosure to the subject, whereinthe administering reduces the side effects when compared toadministering of a once daily oral dose of Zytiga® at 1000 mg withoutfood. Suitable routes of administration, dosing amounts, frequenciesinclude those described herein. Various side effects or adverse effectsare described in the Zytiga® prescribing information approved by theFDA, see e.g., the February 2018 or June 2019 version. In someembodiments, the present disclosure provides a method of treatingsubjects who are also administered a drug, the metabolism of which isinhibited by abiraterone, for example, drugs that are CYP2D6 and/orCYP2C8 substrates, the method comprising administering to the subjectthe abiraterone prodrugs and abiraterone prodrug formulations of thepresent disclosure, wherein the administering reduces the inhibition ofthe metabolism of the drug when compared to administering of a oncedaily oral dose of Zytiga® at 1000 mg without food. In some embodiments,the present disclosure provides a method of treating a subject who has,or is at risk of having, hypertension, hypokalemia, or fluid retentiondue to mineralocorticoid excess, the method comprising administering tothe subject the abiraterone prodrugs and abiraterone prodrugformulations of the present disclosure, wherein the administeringreduces hypertension, hypokalemia, and fluid retention or the risk ofhypertension, hypokalemia, and fluid retention when compared toadministering of a once daily oral dose of Zytiga® at 1000 mg withoutfood. In some embodiments, the present disclosure provides a method oftreating a subject who has, or is at risk of having, adrenocorticalinsufficiency, the method comprising administering to the subject theabiraterone prodrugs and abiraterone prodrug formulations of the presentdisclosure, wherein the administering reduces adrenocorticalinsufficiency or the risk of having adrenocortical insufficiency whencompared to administering of a once daily oral dose of Zytiga® at 1000mg without food. In some embodiments, the present disclosure provides amethod of treating a subject who has severe or fatal hepatotoxicityafter taking Zytiga®, the method comprising administering to the subjectthe abiraterone prodrugs and abiraterone prodrug formulations of thepresent disclosure, wherein the administering reduces hepatotoxicity.Without wishing to be bound by theories, it is believed thatadministering the abiraterone prodrugs and abiraterone prodrugformulations of the present disclosure typically results in a reduced,yet efficacious abiraterone exposure and therefore is beneficial forsubjects who need a lower dose of abiraterone, e.g., as described above.Suitable dosing regimens, routes of administrations include thosedescribed herein.

Abiraterone Decanoate

Some embodiments of the present disclosure are specifically directed toabiraterone decanoate. As discussed in more details in the Examplessection, pharmacokinetic studies show that intramuscular injection ofabiraterone decanoate formulations can provide a therapeuticallyeffective amount of plasma abiraterone for an extended period of time invarious animal models. In the monkey PK studies, it was further shownthat a single intramuscular injection of abiraterone decanoateformulation can achieve a prolonged CYP17A1 inhibition, with sustainedincrease of progesterone level and reduction of cortisol andtestosterone level. Further, based on the PK studies in rats, dogs, andmonkeys, a human PK prediction was made based on allometric scaling. Asshown in FIG. 16C, based on allometric scaling, it was predicted thatfollowing intramuscular doses of abiraterone decanoate, once in every 4weeks with about 1000 mg each dose, to a human, a C_(min) is expected tobe at 5 ng/mL at steady state. Additionally, as detailed in the Examplessection and FIG. 14F, it was unexpectedly found that abirateronedecanoate formulations with certain combination of oil and solvents canachieve significantly higher abiraterone plasma concentrations inmonkeys following IM injections compared to abiraterone decanoateformulation in 90% corn oil and 10% benzyl alcohol at the same dose,with abiraterone decanoate concentration substantially the same. Thus,the dosing amount of abiraterone decanoate needed to achieve thepredicted C_(min) of 5 ng/mL at steady state can be lowered.Alternatively, the steady state C_(min) can also be increased to abovethe predicted level of 5 ng/mL. These disclosures demonstrate thatabiraterone can be delivered in a therapeutically effective amount to asubject (e.g., a human subject) by injection of an abiraterone prodrug,such as an abiraterone lipophilic ester prodrug, more particularly,abiraterone decanoate, with a less frequent dosing than once a week,such as once in two weeks, once a month, or once in more than a month.Typically, the dosing frequency can range from once a week to once everyfew months, such as from once a week to once every eight weeks, or fromonce a week to once every three months, such as once a month, once everyeight weeks, etc.

In some specific embodiments, the present disclosure provides acompound, which is abiraterone decanoate having the formula of:

or a pharmaceutically acceptable salt thereof. In some embodiments,abiraterone decanoate can be in its basic form. In some embodiments,abiraterone decanoate can also be in a pharmaceutically acceptable salt,such as an oxalate salt, a hydrochloride salt, a benzene sulfonate salt,a p-toluene sulfonate salt, a phosphate salt, etc. In some embodiments,the salts of abiraterone decanoate can be used as a syntheticintermediate for the preparation and purification of abirateronedecanoate in its basic form. As discussed herein, abiraterone decanoateis typically present in the abiraterone prodrug formulation herein inits basic form. Unless specifically referred to as in its salt form orotherwise contradictory from context, abiraterone decanoate should beunderstood as in its basic form.

Abiraterone decanoate or its pharmaceutically acceptable salts can bereadily prepared by those skilled in the art in view of the presentdisclosure. Some exemplary methods of synthesis are described herein. Insome embodiments, the present disclosure provides a method ofsynthesizing abiraterone decanoate, which comprises reacting abirateronewith decanoic acid, or an activated form thereof, such as thecorresponding acyl chloride, anhydride (e.g., mixed anhydride), etc. Thereaction can be typically carried out in the presence of a couplingagent, such as a carbodiimide. As shown in the Examples section, thecoupling of abiraterone and decanoic acid can be carried out in thepresence of 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, a base (suchas triethyl amine) and a catalytic amount of DMAP. Salts of abriateronedecanoate can be prepared by reacting abiraterone decanoate with asuitable acid, such as oxalic acid, benzene sulfonic acid, p-toluenesulfonic acid, hydrochloric acid, or phosphoric acid, typically in anorganic solvent such as isopropyl acetate, ethyl acetate, etc.

In some embodiments, abiraterone decanoate can exist in a solid formsuch as a crystalline form, an amorphous form, or a combination thereof.For example, in some embodiments, the present disclosure providesabiraterone decanoate in a crystalline form. In some embodiments, thecrystalline form can be characterized by an X-Ray Power Diffraction(XRPD) spectrum having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9)of the following peaks: 4.6, 6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and20.8, degrees 2 theta, ±0.2°; a Differential Scanning Calorimetry (DSC)pattern having an endothermic peak with an onset temperature at about69.0° C.; or a combination thereof. In some embodiments, the crystallineform can be characterized by an XRPD spectrum substantially the same asshown in FIG. 12A, for example, the XRPD spectrum shows peaks at therespective diffraction angels (degrees 2 theta, ±0.2°) corresponding tothe peaks as shown in FIG. 12A, regardless of their relativeintensities. In some embodiments, the crystalline form can becharacterized by a DSC spectrum substantially the same as shown in FIG.12B.

In some embodiments, the present disclosure also provides a method ofpreparing a crystalline form of abiraterone decanoate. In someembodiments, the method can include recrystallizing abirateronedecanoate in a suitable solvent, such as acetone and water. In a typicalmethod, the abiraterone decanoate can be first dissolved in a firstsolvent, such as acetone, at room temperature or under heat (such asabout 40° C.), to form a solution; the solution can then be cooled toform a suspension; and optionally, this can then be followed by dilutionof the suspension with a second solvent (typically an antisolvent inwhich abiraterone decanoate has a low solubility), such as water, andstirring for a period of time (such as about 12 hours) to form thecrystalline form. The amount of solvent, concentration, etc. can beadjusted by those skilled in the art in view of this disclosure. Anexemplary procedure is also shown in Example 6A.

Abiraterone decanoate is typically prepared in a high purity form, e.g.,suitable for pharmaceutical use. In some embodiments, the presentdisclosure provides abiraterone decanoate in a substantially pure form,such as having a purity of greater than 80%, preferably greater than 90%(e.g., greater than 95%, greater than 97%, greater than 98%, greaterthan 99%, greater than 99.5%), by weight, by HPLC area, or both. In someembodiments, the abiraterone decanoate can be characterized by a purityby weight and/or by HPLC area of about 95%, about 97%, about 99%, about99.5%, about 99.9%, or any ranges between the specified values. Forexample, in some embodiments, the abiraterone decanoate can becharacterized by a purity by weight of about 95%, about 97%, about 99%,about 99.5%, about 99.9%, or any ranges between the specified values.Exemplary procedures for preparing the substantially pure abirateronedecanoate are shown in the Examples section. HPLC methods suitable formeasuring the purity of the abiraterone decanoate are also described inthe Examples section. The substantially pure abiraterone decanoate canbe in a solid form (e.g., a crystalline form described herein, amorphousform, or a combination thereof) or in a solution, suspension, or anotherform. For the avoidance of doubt, an abiraterone prodrug formulationcomprising the substantially pure abiraterone decanoate herein and oneor more other ingredients should be understood as a mixture of thesubstantially pure abiraterone decanoate herein and the one or moreother ingredients, for example, such formulation can be obtaineddirectly or indirectly from mixing (e.g., dissolving, suspending, orotherwise forming a mixture) the substantially pure abirateronedecanoate with the one or more other ingredients, such aspharmaceutically acceptable oil, solvent, etc.

In some specific embodiments, the present disclosure provides apharmaceutical composition comprising abiraterone decanoate having theformula of:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. The abiraterone decanoate is typically present inthe pharmaceutical composition in its basic form and should beunderstood as such unless otherwise obvious to the contrary fromcontext. In some embodiments, the abiraterone decanoate can also be in asubstantially pure form described herein. For example, thepharmaceutical composition can be prepared from mixing the substantiallypure abiraterone decanoate with the pharmaceutically acceptable carrierand optional other ingredients. In some specific embodiments, thesubstantially pure abiraterone decanoate is in a crystalline formdescribed herein, and the pharmaceutical composition can be preparedfrom mixing (e.g., dissolving, suspending, or otherwise forming amixture) the crystalline form with the pharmaceutically acceptablecarrier and optional other ingredients.

Typically, the pharmaceutical composition is formulated for parenteraladministration. For example, in some embodiments, the pharmaceuticalcomposition can be formulated for intramuscular injection, intradermalinjection, or subcutaneous injection.

The pharmaceutical composition is generally a non-aqueous formulation,for example, an oil based formulation, and include a non-aqueouspharmaceutically acceptable carrier (e.g., described herein). Forexample, in some embodiments, the pharmaceutically acceptable carriercomprises a pharmaceutically acceptable oil, such as a pharmaceuticallyacceptable oil for injection, including oils of vegetable origin orsynthetic mono- or diglycerides of fatty acids. In some embodiments, thepharmaceutically acceptable oil can be nature oil, synthetic oil, orsemi-synthetic oil, such as fractionated coconut oil and medium-chaintriglycerides, such as those sold under the trademark Miglyol. In someembodiments, the pharmaceutically acceptable carrier comprises atriglyceride derived from fatty acids. In some embodiments, thepharmaceutically acceptable carrier comprises a triglyceride derivedfrom long and/or medium chain fatty acids, which can be independentlypoly-unsaturated, mono-unsaturated, or saturated. As understood by thoseskilled in the art, medium chain fatty acids typically include 6-12carbons, such as caprioic acid, caprylic acid, capric acid, lauric acid,etc.; short chain fatty acids typically have fewer than 6 carbons;whereas long-chain fatty acids typically include 13-21 carbons. In someembodiments, the pharmaceutically acceptable carrier comprises apharmaceutically acceptable oil, which can be selected from vegetableoil, castor oil, corn oil, sesame oil, cottonseed oil, peanut oil(arachis oil), poppy seed oil, tea seed oil, and soybean oil. In somespecific embodiments, the pharmaceutically acceptable carrier cancomprise corn oil, which includes a triglyceride, in which the fattyacid constituents are primarily linoleic acid, oleic acid, palmiticacid, and stearic acid.

In some embodiments, in addition to the pharmaceutically acceptable oil,the pharmaceutically acceptable carrier can further comprise apharmaceutically acceptable solvent (or co-solvent if the oil is countedas a solvent), such as an alcohol, ester, acid, etc. In someembodiments, the pharmaceutically acceptable solvent can include benzylalcohol, benzyl benzoate, ethanol, glycerol, polyethylene glycol,polysorbate 80, acetic acid, and/or ethyl acetate. In some embodiments,the pharmaceutically acceptable solvent can be benzyl alcohol and/orbenzyl benzoate. In some embodiments, the pharmaceutically acceptablesolvent can be benzyl alcohol. In some embodiments, the pharmaceuticallyacceptable solvent can be a combination of benzyl alcohol and benzylbenzoate. As discussed herein, the solubility of abiraterone decanoatein a pharmaceutically acceptable oil can be significantly enhanced by acombination of benzyl alcohol and benzyl benzoate.

In some specific embodiments, the present disclosure provides apharmaceutical composition comprising abiraterone decanoate, apharmaceutically acceptable oil (e.g., described herein), benzylalcohol, and benzyl benzoate. In some embodiments, the pharmaceuticallyacceptable oil is corn oil. In some embodiments, the benzyl alcohol ispresent in an amount of about 5-10% by volume, the benzyl benzoate ispresent in an amount of about 10-20% by volume, and corn oil is presentin an amount of about 70-85% by volume, with the combined volume ofbenzyl alcohol, benzyl benzoate, and corn oil being 100%.

The pharmaceutical composition typically include abiraterone decanoateat a concentration of about 25 mg/ml to about 500 mg/ml. In someembodiments, the abiraterone decanoate can be present in a concentrationof about 50 mg/ml, about 100 mg/ml, about 150 mg/ml, about 200 mg/ml,about 250 mg/ml, about 300 mg/ml, about 350 mg/ml, about 400 mg/ml,about 500 mg/ml, or any ranges between the recited values. In someembodiments, the abiraterone decanoate can be present in a concentrationof about 100 mg/ml to about 300 mg/ml, such as about 150 mg/ml to about250 mg/ml, about 200 mg/ml to about 300 mg/ml, etc.

The abiraterone decanoate in the pharmaceutical composition is typicallyincluded in a therapeutically effective amount for treating a disease ordisorder described herein, such as prostate cancer. In some embodiments,the abiraterone decanoate can be present in the pharmaceuticalcomposition in an amount sufficient to provide a therapeuticallyeffective blood plasma concentration of abiraterone for a period of atleast one week, e.g., at least two weeks, at least four weeks, and up tosix or eight weeks or more, after a single administration to a subjecthaving a sex hormone-dependent benign or malignant disorder, a syndromedue to androgen excess, and/or a syndrome due to glucocorticoid excesssuch as hypercortisolemia. In some embodiments, the abirateronedecanoate can be present in the pharmaceutical composition in an amountsufficient to provide a therapeutically effective blood plasmaconcentration of abiraterone at about 1 ng/ml or higher, such as about 2ng/ml or higher, about 4 ng/ml or higher, about 5 ng/ml or higher, about8 ng/ml or higher, etc. for a period of at least one week, e.g., atleast two weeks, at least four weeks, and up to six or eight weeks ormore, after a single administration to a subject having a sexhormone-dependent benign or malignant disorder, a syndrome due toandrogen excess, and/or a syndrome due to glucocorticoid excess such ashypercortisolemia. In some embodiments, the abiraterone decanoate can bepresent in the pharmaceutical composition in an amount sufficient toprovide a therapeutically effective blood plasma concentration ofabiraterone at about 0.5 ng/ml or higher for a period of at least fourweeks, e.g., at least six weeks and up to eight weeks or more, after asingle administration to a subject having a sex hormone-dependent benignor malignant disorder, a syndrome due to androgen excess, and/or asyndrome due to glucocorticoid excess such as hypercortisolemia.

In some specific embodiments, the present disclosure provides apharmaceutical composition, e.g., unit dosage form, comprising atherapeutically effective amount of abiraterone decanoate having theformula of:

a pharmaceutically acceptable oil, and a pharmaceutically acceptablesolvent, wherein the abiraterone decanoate is in its basic form, whichis present at a concentration of about 25 mg/ml to about 500 mg/ml, suchas about 50 mg/ml, about 100 mg/ml, about 150 mg/ml, about 200 mg/ml,about 250 mg/ml, about 300 mg/ml, about 350 mg/ml, about 400 mg/ml,about 500 mg/ml, or any ranges between the recited values, wherein thepharmaceutical composition, e.g., unit dosage form, is formulated forparenteral injection, such as intramuscular injection, intradermalinjection, or subcutaneous injection, wherein the pharmaceuticalcomposition, e.g., unit dosage form, comprises the abiraterone decanoatein an amount of about 50 mg to about 2,000 mg, such as about 100 mg,about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, about 2000 mg,or any ranges between the recited values. In some embodiments, thepharmaceutical composition can be in a unit dosage form. Typically,depending on the dosing amount, one or more (e.g., 1) of the unit dosageforms can be administered to a subject in need thereof. Thepharmaceutically acceptable oil in the pharmaceutical composition, e.g.,unit dosage form, can be any of those described herein. For example, insome embodiments, the pharmaceutically acceptable oil is apharmaceutically acceptable oil for injection, including oils ofvegetable origin or synthetic mono- or diglycerides of fatty acids. Insome embodiments, the pharmaceutically acceptable oil can be nature oil,synthetic oil, or semi-synthetic oil, such as fractionated coconut oiland medium-chain triglycerides, such as those sold under the trademarkMiglyol. In some embodiments, the pharmaceutically acceptable oil cancomprise a triglyceride derived from fatty acids. In some embodiments,the pharmaceutically acceptable oil can comprise a triglyceride derivedfrom long and/or medium chain fatty acids, which can be independentlypoly-unsaturated, mono-unsaturated, or saturated. In some embodiments,the pharmaceutically acceptable oil can be selected from vegetable oil,castor oil, corn oil, sesame oil, cottonseed oil, peanut oil (arachisoil), poppy seed oil, tea seed oil, and soybean oil. In some specificembodiments, the pharmaceutically acceptable oil can comprise corn oil,which includes a triglyceride, in which the fatty acid constituents areprimarily linoleic acid, oleic acid, palmitic acid, and stearic acid.The pharmaceutically acceptable solvent in the pharmaceuticalcomposition, e.g., unit dosage form, also include any of those describedherein. In some embodiments, the pharmaceutically acceptable solvent (orco-solvent if the oil is counted as a solvent), such as an alcohol,ester, acid, etc. In some embodiments, the pharmaceutically acceptablesolvent can include benzyl alcohol, benzyl benzoate, ethanol, glycerol,polyethylene glycol, polysorbate 80, acetic acid, and/or ethyl acetate.In some embodiments, the pharmaceutically acceptable solvent can bebenzyl alcohol and/or benzyl benzoate. In some embodiments, thepharmaceutical composition, e.g., unit dosage form, comprisesabiraterone decanoate, a pharmaceutically acceptable oil (e.g.,described herein), benzyl alcohol, and benzyl benzoate. In someembodiments, the pharmaceutically acceptable oil is corn oil. In someembodiments, the benzyl alcohol is present in an amount of about 5-10%by volume, the benzyl benzoate is present in an amount of about 10-20%by volume, and corn oil is present in an amount of about 70-85% byvolume, with the combined volume of benzyl alcohol, benzyl benzoate, andcorn oil being 100%.

In some embodiments, the present disclosure provides exemplaryabiraterone decanoate formulations as shown in Table C. All numericvalues in the table should be understood as preceded by the term“about.” The concentration of abiraterone decanoate refers to the amountof abiraterone decanoate in mg per ml of the final formulation, whichcan be a solution or suspension. The amount of oil (the primary solvent)and co-solvent (benzyl alcohol and/or benzyl benzoate) in the tables isexpressed as volume percentage of solvent, which includes both the oiland co-solvent. Suitable oil include any of the pharmaceuticallyacceptable oil as described herein, such as corn oil. Optionaladditional ingredients are not shown in Table C. Examples 3F-3H hereinshow procedures of preparing representative abiraterone decanoateformulations of Table C.

TABLE C Exemplary Abiraterone Decanoate FormulationsAmount/Concentration More Exemplary Ingredients Typical Exemplary rangeRange Abiraterone 25 mg/ml to 500 50 mg/ml to 300 75 mg/ml to 300decanoate mg/ml mg/ml; 100 mg/ml to mg/ml, such as 150 300 mg/ml mg/mlto about 250 mg/ml Oil (e.g., corn oil, 30% to 100% of 50% to 90% ofsolvent 60% to 90% of castor oil, sesame oil, solvent solvent, such as70% peanut oil, cottonseed oil, and/or Miglyol 812) benzyl alcohol 0% to20% of solvent 0% to 15% of solvent 0% to 10% of solvent, such as 10%benzyl benzoate 0% to 50% of solvent 0% to 35% of solvent 0% to 30% ofsolvent, such as 20%

The pharmaceutical composition or unit dosage form herein can beprepared by those skilled in the art in view of the methods disclosedherein. In some embodiments, the present disclosure provides a methodfor preparing an abiraterone decanoate formulation suitable forparenteral administration to a subject having a sex hormone-dependentbenign or malignant disorder, a syndrome due to androgen excess, and/ora syndrome due to glucocorticoid excess such as hypercortisolemia. Insome embodiments, the method comprises mixing (such as dissolving orsuspending) abiraterone decanoate, which has the formula of:

in a pharmaceutically acceptable carrier to form a mixture (such as asolution or suspension). In some embodiments, the method furthercomprises sterilizing the mixture (e.g., solution or suspension). Insome embodiments, the dissolving or suspending can comprise mixing(e.g., dissolving or suspending) the crystalline form of abirateronedecanoate described herein in the pharmaceutically acceptable carrier.In some embodiments, the mixing (such as dissolving or suspending) cancomprise mixing (e.g., dissolving or suspending) the substantially pureabiraterone decanoate described herein in the pharmaceuticallyacceptable carrier. Suitable pharmaceutically acceptable carriers andamounts, amount of abiraterone decanoate, concentration of abirateronedecanoate, include any of those described herein. For example, in someembodiments, the pharmaceutically acceptable carrier comprises apharmaceutically acceptable oil and a pharmaceutically acceptablesolvent, wherein the pharmaceutically acceptable oil comprises avegetable oil, castor oil, corn oil, sesame oil, cottonseed oil, peanutoil, poppy seed oil, tea seed oil, or soybean oil, the pharmaceuticallyacceptable solvent comprises benzyl alcohol and/or benzyl benzoate, andwherein the abiraterone decanoate is present at a concentration of about50 mg/mL to about 300 mg/mL such as about 100 mg/mL to about 300 mg/mL.

In some specific embodiments, the present disclosure also provides amethod of treating a sex hormone-dependent benign or malignant disorder,a syndrome due to androgen excess, and/or a syndrome due toglucocorticoid excess such as hypercortisolemia, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the pharmaceutical composition comprising abirateronedecanoate described herein (e.g., the unit dosage form describedherein). The administering is not limited to any particular route.However, the abiraterone decanoate is typically administeredparenterally, for example, via an intramuscular injection, intradermalinjection, or subcutaneous injection. In some embodiments, theadministering is through intramuscular injection. Unlike oraladministration of abiraterone acetate, the pharmaceutical compositioncomprising abiraterone decanoate described herein (e.g., the unit dosageform described herein) can be administered to the subject in need withor without food.

Sex hormone-dependent benign or malignant disorder that can be treatedwith the methods include any of those described herein. In someembodiments, the sex hormone-dependent benign or malignant disorders canbe selected from androgen-dependent disorders and estrogen-dependentdisorders such as androgen-dependent or estrogen-dependent cancers. Insome embodiments, the sex hormone-dependent benign or malignantdisorders can be selected from prostate cancer, breast cancer, ovariancancer, bladder cancer, hepatocellular carcinoma, and lung cancer, etc.In some embodiments, the sex hormone-dependent benign or malignantdisorder can be prostate cancer or breast cancer. In some embodiments,the sex hormone-dependent benign or malignant disorder is castrationresistant prostate cancer or castration sensitive prostate cancer. Insome embodiments, the sex hormone-dependent benign or malignant disordercan be metastatic castration resistant prostate cancer or metastaticcastration sensitive prostate cancer. Syndromes due to androgen excessand/or syndromes due to glucocorticoid excess such as hypercortisolemiathat can be treated with the methods include any of those describedherein. In some embodiments, the method herein can be a method fortreating a non-oncologic syndrome in the subject due to androgen excess,such as endometriosis, polycystic ovary syndrome, congenital adrenalhyperplasia (e.g., classical or nonclassical congenital adrenalhyperplasia), precocious puberty, hirsutism, etc. In some embodiments,the method herein can be a method for treating a non-oncologic syndromedue to glucocorticoid (e.g., cortisole) excess, such as Cushing'ssyndrome or Cushing's disease.

The methods herein can be used in conjunction with one or moreadditional therapies for the respective disease or disorder. Forexample, the method can comprise administering one or more other drug oragent (for example, as described herein, such as another cancerchemotherapeutic drug, hormone replacement drug, or hormone ablationdrug) to the subject, either concurrently or sequentially, through thesame route or a different route of administration. In some embodiments,the subject can also be treated with a gonadotropin-releasing hormoneanalog and/or bilateral orchiectomy.

As discussed herein, abiraterone is a 17α-hydroxylase/C17,20-lyase(CYP17) inhibitor, which can lead to reduction in biosynthesis ofandrogens (such as testosterone), reduction in glucocorticoids (such ascortisol), and an mineralocorticoid excess (e.g., increase inprogesterone). Adrenal insufficiency has also been noted to beassociated with abiraterone therapy, such as Zytiga®. Intramuscularadministration of a pharmaceutical composition comprising abirateronedecanoate herein was shown to provide an effective plasma level ofabiraterone and inhibit CYP17A1 in vivo for a prolonged period of time,with an increase in progesterone level and a reduction in cortisollevel.

In some embodiments, the method herein (e.g., treating a prostatecancer, or treating classical or nonclassical congenital adrenalhyperplasia) can comprise administering to the subject an agent thatoffsets the reduction of glucocorticoid(s) associated with theadministration of abiraterone decanoate as described herein. In someembodiments, the method can comprise administering to the subject inneed an agent effective in treating one or more symptoms associated withadrenal insufficiency, such as acute stress, fatigue, etc. In somespecific embodiments, the method can comprise administering to thesubject a steroid, such as a corticosteroid. In some embodiments, themethod can comprise administering to the subject a glucocorticoid. Insome specific embodiments, the method also comprises administering tothe subject prednisone, prednisolone, and/or methylprednisolone. In someembodiments, the method also comprises administering to the subject anagent effective in treating cortisol deficiency, for example,hydrocortisone, prednisone, prednisolone, methylprednisolone, and/ordexamethasone. In any such embodiments, the agent can be administered tothe subject either concurrently or sequentially in any order, via a sameor different route of administration.

In some embodiments, the methods herein can be characterized by a dosingfrequency of once a week or even less frequent. Typically, the dosingfrequency can range from once a week to once every few months, such asfrom once a week to once every three months, or from once a week to onceevery eight weeks, such as once a month. In some embodiments, the methodcomprises administering to the subject the pharmaceutical compositioncomprising abiraterone decanoate (e.g., the unit dosage form describedherein) once a week, once in two weeks, once in three weeks, once amonth, or once in more than a month. In some embodiments, the methodcomprises administering to the subject the pharmaceutical compositioncomprising abiraterone decanoate (e.g., the unit dosage form describedherein) once in two weeks, once a month, or once in more than a month.In some embodiments, the dosing amount for each dose is about 50 mg toabout 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about1000 mg, about 1500 mg, or any ranges between the recited values) ofabiraterone decanoate. In some embodiments, the dosing amount ofabiraterone decanoate for each dose is about 0.5 mg/kg to about 100mg/kg (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg,about 100 mg/kg, or any ranges between the recited values) of bodyweight of a subject. In some embodiments, the administering is viaintramuscular injection. In some embodiments, the administering providesa therapeutically effective blood plasma concentration of abiraterone aperiod of at least one week, e.g., at least two weeks, such as at leastthree weeks, at least four weeks, and up to six or eight weeks or more,etc. In some embodiments, the administering provides a blood plasmaconcentration of abiraterone above 1.0 ng/ml (e.g., between about 1ng/ml and about 8 ng/ml, or about 2 ng/ml or higher, about 4 ng/ml orhigher, about 5 ng/ml or higher, or about 8 ng/ml or higher) for aperiod of at least one week, e.g., at least two weeks, such as at least3 weeks, at least four weeks, and up to six or eight weeks or more, etc.In some embodiments, the administering provides a steady state C_(min)of abiraterone above 1.0 ng/ml (e.g., between about 1 ng/ml and about 8ng/ml, about 2 ng/ml or higher, about 4 ng/ml or higher, about 5 ng/mlor higher, or about 8 ng/ml or higher). In some embodiments, theadministering provides a single dose or steady state C_(max) ofabiraterone between about 10 ng/ml and about 400 ng/ml, such as about 10ng/ml, about 15 ng/ml, about 20 ng/ml, about 30 ng/ml, about 50 ng/ml,about 60 ng/ml, about 100 ng/ml, about 150 ng/ml, about 160 ng/ml, orany ranges recited between the values, for example, about 10-30 ng/ml,about 20-60 ng/ml, about 15-160 ng/ml or about 50-100 ng/ml. In someembodiments, the abiraterone decanoate formulation can be administeredto the subject in need thereof as the only source of abiraterone.However, in some embodiments, the abiraterone decanoate formulation canalso be administered to the subject in need thereof as a supplement toanother abiraterone therapy.

In some specific example, the present disclosure provides a method oftreating prostate cancer, the method comprising administering to asubject in need thereof abiraterone decanoate via intramuscularinjection, intradermal injection, or subcutaneous injection, once a weekor once in more than a week, such as once a month or once in more than amonth, with each dose at about 50 mg to about 2000 mg (e.g., about 100mg, about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or anyranges between the recited values) of abiraterone decanoate. In someembodiments, the abiraterone decanoate is administered via intramuscularinjection. In some embodiments, the prostate cancer is castrationresistant prostate cancer or castration sensitive prostate cancer. Insome embodiments, the prostate cancer is metastatic castration resistantprostate cancer or metastatic castration sensitive prostate cancer.

In some specific example, the present disclosure provides a method oftreating prostate cancer, the method comprising administering to asubject in need thereof the pharmaceutical composition comprisingabiraterone decanoate described herein (e.g., the unit dosage formdescribed herein) via intramuscular injection, intradermal injection, orsubcutaneous injection, once a week or once in more than a week, such asonce a month or once in more than a month, with each dose at about 50 mgto about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about1000 mg, about 1500 mg, or any ranges between the recited values) ofabiraterone decanoate or with each dose of abiraterone decanoate atabout 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg, about 1mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg,about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any ranges betweenthe recited values) of body weight of the subject. In some embodiments,the pharmaceutical composition is administered via intramuscularinjection. In some embodiments, the prostate cancer is castrationresistant prostate cancer or castration sensitive prostate cancer. Insome embodiments, the prostate cancer is metastatic castration resistantprostate cancer or metastatic castration sensitive prostate cancer.

In some specific example, the present disclosure provides a method oftreating prostate cancer, the method comprising administering to asubject in need thereof the unit dosage form described herein viaintramuscular injection, intradermal injection, or subcutaneousinjection, once a week or once in more than a week, such as once a monthor once in more than a month, with each dose at about 50 mg to about2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg,about 1500 mg, or any ranges between the recited values) of abirateronedecanoate or with each dose of abiraterone decanoate at about 0.5 mg/kgto about 100 mg/kg (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg,about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90mg/kg, about 100 mg/kg, or any ranges between the recited values) ofbody weight of the subject. In some embodiments, the unit dosage form isadministered via intramuscular injection. In some embodiments, theprostate cancer is castration resistant prostate cancer or castrationsensitive prostate cancer. In some embodiments, the prostate cancer ismetastatic castration resistant prostate cancer or metastatic castrationsensitive prostate cancer.

In some specific embodiments, the present disclosure also provides amethod of delivering abiraterone to a subject in need thereof, themethod comprising administering to the subject the pharmaceuticalcomposition comprising abiraterone decanoate described herein (e.g., theunit dosage form described herein) via intramuscular injection,intradermal injection, or subcutaneous injection, once a week or once inmore than a week, such as once a month or once in more than a month,with each dose at about 50 mg to about 2000 mg (e.g., about 100 mg,about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any rangesbetween the recited values) of abiraterone decanoate or with each doseof abiraterone decanoate at about 0.5 mg/kg to about 100 mg/kg (e.g.,about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg,or any ranges between the recited values) of body weight of the subject.In some embodiments, the pharmaceutical composition is administered viaintramuscular injection. In some embodiments, the subject suffers from ahormone-dependent benign or malignant disorder, a syndrome due toandrogen excess, and/or a syndrome due to glucocorticoid excess such ashypercortisolemia, e.g., as described herein.

In some specific embodiments, the present disclosure also provides amethod of inhibiting CYP17A1 activity in a subject in need thereof, themethod comprising administering to the subject the pharmaceuticalcomposition comprising abiraterone decanoate described herein (e.g., theunit dosage form described herein) via intramuscular injection,intradermal injection, or subcutaneous injection, once a week or once inmore than a week, such as once a month or once in more than a month,with each dose at about 50 mg to about 2000 mg (e.g., about 100 mg,about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any rangesbetween the recited values) of abiraterone decanoate or with each doseof abiraterone decanoate at about 0.5 mg/kg to about 100 mg/kg (e.g.,about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg,or any ranges between the recited values) of body weight of the subject.In some embodiments, the pharmaceutical composition is administered viaintramuscular injection. In some embodiments, the subject suffers from asex hormone-dependent benign or malignant disorder, e.g., as describedherein. In some embodiments, the subject suffers from a syndrome due toandrogen excess and/or a syndrome due to glucocorticoid excess such ashypercortisolemia, e.g., as described herein.

In some specific embodiments, the present disclosure also provides amethod of reducing the level of glucocorticoids (e.g., cortisol) in asubject in need thereof in a subject in need thereof, the methodcomprising administering to the subject the pharmaceutical compositioncomprising abiraterone decanoate described herein (e.g., the unit dosageform described herein) via intramuscular injection, intradermalinjection, or subcutaneous injection, once a week or once in more than aweek, such as once a month or once in more than a month, with each doseat about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about500 mg, about 1000 mg, about 1500 mg, or any ranges between the recitedvalues) of abiraterone decanoate or with each dose of abirateronedecanoate at about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg,about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any rangesbetween the recited values) of body weight of the subject. In someembodiments, the pharmaceutical composition is administered viaintramuscular injection. In some embodiments, the subject suffers from ahypercortisolemia as described herein, such as Cushing's syndrome orCushing's disease.

In some specific embodiments, the present disclosure also provides amethod of reducing the level of androgens (e.g., testosterone and/ordihydrotestosterone) and/or estrogens in a subject in need thereof in asubject in need thereof, the method comprising administering to thesubject the pharmaceutical composition comprising abiraterone decanoatedescribed herein (e.g., the unit dosage form described herein) viaintramuscular injection, intradermal injection, or subcutaneousinjection, once a week or once in more than a week, such as once a monthor once in more than a month, with each dose at about 50 mg to about2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about 1000 mg,about 1500 mg, or any ranges between the recited values) of abirateronedecanoate or with each dose of abiraterone decanoate at about 0.5 mg/kgto about 100 mg/kg (e.g., about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg,about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 50 mg/kg, about 90mg/kg, about 100 mg/kg, or any ranges between the recited values) ofbody weight of the subject. In some embodiments, the pharmaceuticalcomposition is administered via intramuscular injection. In someembodiments, the subject suffers from a syndrome due to androgen excess,such as congenital adrenal hyperplasia (e.g., classical or nonclassicalcongenital adrenal hyperplasia), endometriosis, polycystic ovarysyndrome precocious puberty, hirsutism, etc. In some embodiments, thesubject suffers from an androgen and/or estrogen associated cancer, suchas prostate cancer or breast cancer.

Other Abiraterone Prodrugs

While the present disclosure describes embodiments relating toabiraterone decanoate in more details, those skilled in the art wouldunderstand similar embodiments are also applicable to other abirateroneprodrugs of the present disclosure in view of the descriptions herein.For example, like abiraterone decanoate, pharmacokinetics studies showthat intramuscular injection of abiraterone isocaproate formulations canalso provide a therapeutically effective amount of plasma abirateronefor an extended period of time. Thus, embodiments described hereinspecifically to abiraterone decanoate formulations and methods oftreatment can also be similarly applicable to abiraterone isocaproate,with abiraterone decanoate replaced with abiraterone isocaproate.

For example, in some embodiments, the present disclosure also provides amethod of treating a sex hormone-dependent benign or malignant disorder,a syndrome due to androgen excess, and/or a syndrome due toglucocorticoid excess such as hypercortisolemia, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the pharmaceutical composition comprising abirateroneisocaproate described herein (e.g., the unit dosage form describedherein). In some embodiments, the pharmaceutical composition comprisingabiraterone isocaproate described herein (e.g., the unit dosage formdescribed herein) can be administered to the subject in need with orwithout food. Suitable sex hormone-dependent benign or malignantdisorders, syndromes due to androgen excess, syndromes due toglucocorticoid excess such as hypercortisolemia, dosing regimen,combination therapies, etc. include those described herein, e.g., inconnection with abiraterone decanoate.

In some specific example, the present disclosure provides a method oftreating prostate cancer, the method comprising administering to asubject in need thereof the pharmaceutical composition comprisingabiraterone isocaproate described herein via intramuscular injection,intradermal injection, or subcutaneous injection, once a week or once inmore than a week, such as once a month or once in more than a month,with each dose at about 50 mg to about 2000 mg (e.g., about 100 mg,about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any rangesbetween the recited values) of abiraterone isocaproate or with each doseof abiraterone isocaproate at about 0.5 mg/kg to about 100 mg/kg (e.g.,about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg,or any ranges between the recited values) of body weight of the subject.In some embodiments, the pharmaceutical composition is administered viaintramuscular injection. In some embodiments, the prostate cancer iscastration resistant prostate cancer or castration sensitive prostatecancer. In some embodiments, the prostate cancer is metastaticcastration resistant prostate cancer or metastatic castration sensitiveprostate cancer.

In some specific example, the present disclosure provides a method oftreating prostate cancer, the method comprising administering to asubject in need thereof the unit dosage form comprising abirateroneisocaproate described herein via intramuscular injection, intradermalinjection, or subcutaneous injection, once a week or once in more than aweek, such as once a month or once in more than a month, with each doseat about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about500 mg, about 1000 mg, about 1500 mg, or any ranges between the recitedvalues) of abiraterone isocaproate or with each dose of abirateroneisocaproate at about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg,about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or anyranges between the recited values) of body weight of the subject. Insome embodiments, the unit dosage form is administered via intramuscularinjection. In some embodiments, the prostate cancer is castrationresistant prostate cancer or castration sensitive prostate cancer. Insome embodiments, the prostate cancer is metastatic castration resistantprostate cancer or metastatic castration sensitive prostate cancer.

In some specific embodiments, the present disclosure also provides amethod of delivering abiraterone to a subject in need thereof, themethod comprising administering to the subject the pharmaceuticalcomposition comprising abiraterone isocaproate described herein (e.g.,the unit dosage form described herein) via intramuscular injection,intradermal injection, or subcutaneous injection, once a week or once inmore than a week, such as once a month or once in more than a month,with each dose at about 50 mg to about 2000 mg (e.g., about 100 mg,about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any rangesbetween the recited values) of abiraterone isocaproate or with each doseof abiraterone isocaproate at about 0.5 mg/kg to about 100 mg/kg (e.g.,about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg,or any ranges between the recited values) of body weight of the subject.In some embodiments, the pharmaceutical composition is administered viaintramuscular injection. In some embodiments, the subject suffers from ahormone-dependent benign or malignant disorder, a syndrome due toandrogen excess, and/or a syndrome due to glucocorticoid excess such ashypercortisolemia, e.g., as described herein.

In some specific embodiments, the present disclosure also provides amethod of inhibiting CYP17A1 activity in a subject in need thereof, themethod comprising administering to the subject the pharmaceuticalcomposition comprising abiraterone isocaproate described herein (e.g.,the unit dosage form described herein) via intramuscular injection,intradermal injection, or subcutaneous injection, once a week or once inmore than a week, such as once a month or once in more than a month,with each dose at about 50 mg to about 2000 mg (e.g., about 100 mg,about 350 mg, about 500 mg, about 1000 mg, about 1500 mg, or any rangesbetween the recited values) of abiraterone isocaproate or with each doseof abiraterone isocaproate at about 0.5 mg/kg to about 100 mg/kg (e.g.,about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20mg/kg, about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg,or any ranges between the recited values) of body weight of the subject.In some embodiments, the pharmaceutical composition is administered viaintramuscular injection. In some embodiments, the subject suffers from asex hormone-dependent benign or malignant disorder, e.g., as describedherein. In some embodiments, the subject suffers from syndromes due toandrogen excess and/or syndromes due to glucocorticoid excess such ashypercortisolemia, e.g., as described herein.

In some specific embodiments, the present disclosure also provides amethod of reducing the level of glucocorticoids (e.g., cortisol) in asubject in need thereof in a subject in need thereof, the methodcomprising administering to the subject the pharmaceutical compositioncomprising abiraterone isocaproate described herein (e.g., the unitdosage form described herein) via intramuscular injection, intradermalinjection, or subcutaneous injection, once a week or once in more than aweek, such as once a month or once in more than a month, with each doseat about 50 mg to about 2000 mg (e.g., about 100 mg, about 350 mg, about500 mg, about 1000 mg, about 1500 mg, or any ranges between the recitedvalues) of abiraterone isocaproate or with each dose of abirateroneisocaproate at about 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg,about 30 mg/kg, about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or anyranges between the recited values) of body weight of the subject. Insome embodiments, the pharmaceutical composition is administered viaintramuscular injection. In some embodiments, the subject suffers from ahypercortisolemia as described herein, such as Cushing's syndrome orCushing's disease.

In some specific embodiments, the present disclosure also provides amethod of reducing the level of androgens (e.g., testosterone and/ordihydrotestosterone) and/or estrogens in a subject in need thereof in asubject in need thereof, the method comprising administering to thesubject the pharmaceutical composition comprising abirateroneisocaproate described herein (e.g., the unit dosage form describedherein) via intramuscular injection, intradermal injection, orsubcutaneous injection, once a week or once in more than a week, such asonce a month or once in more than a month, with each dose at about 50 mgto about 2000 mg (e.g., about 100 mg, about 350 mg, about 500 mg, about1000 mg, about 1500 mg, or any ranges between the recited values) ofabiraterone isocaproate or with each dose of abiraterone isocaproate atabout 0.5 mg/kg to about 100 mg/kg (e.g., about 0.5 mg/kg, about 1mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg,about 50 mg/kg, about 90 mg/kg, about 100 mg/kg, or any ranges betweenthe recited values) of body weight of the subject. In some embodiments,the pharmaceutical composition is administered via intramuscularinjection. In some embodiments, the subject suffers from a syndrome dueto androgen excess, such as congenital adrenal hyperplasia (e.g.,classical or nonclassical congenital adrenal hyperplasia),endometriosis, polycystic ovary syndrome precocious puberty, hirsutism,etc. In some embodiments, the subject suffers from an androgen and/orestrogen associated cancer, such as prostate cancer or breast cancer.

NON-LIMITING EXEMPLARY EMBODIMENTS

In some embodiments, the present disclosure also provides non-limitingexemplary Embodiments 1-66 as shown below:

Embodiment 1

-   -   An abiraterone prodrug formulation suitable for parenteral        administration to a subject having a hormone-dependent benign or        malignant disorder, comprising:        -   (a) one or more lipophilic-ester forms of abiraterone, and        -   (b) one or more pharmaceutically acceptable carriers,            diluents, or excipients, wherein upon said administration to            said subject, said abiraterone prodrug formulation achieves            a therapeutic blood plasma concentration of abiraterone.

Embodiment 2

-   -   The abiraterone prodrug formulation of Embodiment 1, wherein        said therapeutic blood plasma concentration of abiraterone is at        least 1.0 ng/ml.

Embodiment 3

-   -   The abiraterone prodrug formulation of Embodiment 1, wherein        said therapeutic blood plasma concentration of abiraterone is at        least 8 ng/ml.

Embodiment 4

-   -   The abiraterone prodrug formulation of Embodiment 1, wherein        said therapeutic blood plasma concentration of abiraterone        persists for at least two weeks.

Embodiment 5

-   -   The abiraterone prodrug formulation of Embodiment 1, wherein        said parenteral administration is selected from the group        consisting of intramuscular injection, intradermal injection,        and subcutaneous injection.

Embodiment 6

-   -   The abiraterone prodrug formulation of Embodiment 1, wherein        said lipophilic-ester form is selected from the group consisting        of acetate, propionate, butanoate, valerate, caproate,        enanthate, cypionate, isocaproate, buciclate,        cyclohexanecarboxylate, phenyl propionate, decanoate and        undecanoate.

Embodiment 7

-   -   The abiraterone prodrug formulation of Embodiment 1, wherein        said hormone-dependent benign or malignant disorder is selected        from the group consisting of androgen-dependent disorders and        estrogen-dependent disorders.

Embodiment 8

-   -   The abiraterone prodrug formulation of Embodiment 1, wherein        said hormone-dependent benign or malignant disorder is selected        from the group consisting of prostate cancer and breast cancer.

Embodiment 9

-   -   The abiraterone prodrug formulation of Embodiment 8, wherein        said prostate cancer is selected from the group consisting of        castration resistant prostate cancer and castration sensitive        prostate cancer.

Embodiment 10

-   -   A method for treating a hormone-dependent benign or malignant        disorder comprising parenterally administering to a subject in        need of such treatment an effective dose of at least one        abiraterone prodrug formulation comprising:        -   (a) one or more lipophilic-ester forms of abiraterone, and        -   (b) one or more pharmaceutically acceptable carriers,            diluents, or excipients, wherein upon said administration,            said at least one abiraterone prodrug formulation achieves a            therapeutic blood plasma concentration of abiraterone.

Embodiment 11

-   -   The method of Embodiment 10, wherein said therapeutic blood        plasma concentration of abiraterone is at least 1.0 ng/ml.

Embodiment 12

-   -   The method of Embodiment 10, wherein said therapeutic blood        plasma concentration of abiraterone is at least 8.0 ng/ml.

Embodiment 13

-   -   The method of Embodiment 10, wherein said therapeutic blood        plasma concentration of abiraterone persists for at least two        weeks.

Embodiment 14

-   -   The method of Embodiment 10, wherein said parenteral        administration is selected from the group consisting of        intramuscular injection, intradermal injection, and subcutaneous        injection.

Embodiment 15

-   -   The method of Embodiment 10, wherein said lipophilic-ester form        is selected from the group consisting of acetate, propionate,        butanoate, valerate, caproate, enanthate, cypionate,        isocaproate, buciclate, cyclohexanecarboxylate, phenyl        propionate, decanoate and undecanoate.

Embodiment 16

-   -   The method of Embodiment 10, wherein said hormone-dependent        benign or malignant disorder is selected from the group        consisting of androgen-dependent disorders and        estrogen-dependent disorders.

Embodiment 17

-   -   The method of Embodiment 10, wherein said hormone-dependent        benign or malignant disorder is selected from the group        consisting of prostate cancer and breast cancer.

Embodiment 18

-   -   The method of Embodiment 17, wherein said prostate cancer is        selected from the group consisting of castration resistant        prostate cancer and castration sensitive prostate cancer.

Embodiment 19

-   -   The method of Embodiment 10, wherein the method further        comprises once-monthly administration of said at least one        abiraterone prodrug formulation.

Embodiment 20

-   -   The method of Embodiment 10, wherein said at least one        abiraterone prodrug formulation is administered in a divided        dose.

Embodiment 21

-   -   The method of Embodiment 10, wherein said at least one        abiraterone prodrug formulation is administered simultaneously        with at least one other drug or agent.

Embodiment 22

-   -   The method of Embodiment 10, wherein said at least one        abiraterone prodrug formulation is administered before at least        one other drug or agent.

Embodiment 23

-   -   The method of Embodiment 10, wherein said at least one        abiraterone prodrug formulation is administered after at least        one other drug or agent.

Embodiment 24

-   -   A kit for treating the hormone-dependent benign or malignant        disorder of Embodiment 10, comprising at least one abiraterone        prodrug formulation.

Embodiment 25

-   -   A method for preparing an abiraterone decanoate formulation        suitable for parenteral administration to a subject having a        hormone-dependent benign or malignant disorder, comprising the        steps of:        -   (a) preparing and purifying abiraterone decanoate,        -   (b) preparing an oil and co-solvent mixture,        -   (c) combining said prepared and purified abiraterone            decanoate with one of said oil and alcohol mixture from step            (b),        -   (d) sterilizing the mixture formed in step (c), and        -   (e) optionally combining the sterilized mixture of step (d)            with one or more pharmaceutically acceptable carriers,            diluents, or excipients.

Embodiment 26

-   -   The method of Embodiment 25, wherein said prepared and purified        abiraterone decanoate has the following chemical properties:        LCMS m/z 504.4 (M+H); ¹H NMR (CDCl₃, 200 MHz): δH 0.877 (3H, t,        J=7 Hz), 1.043 (3H, s), 1.082 (3H, s), 1.268 (16H, m), 1.643        (15H, m), 1.842 (3H, m), 2.065 (3H, m), 2.290 (5H, m), 4.602        (1H, m), 5.404 (1H, d, J=5 Hz), 5.998 (1H, q, J=5 Hz), 7.215        (1H, ddd, J=1, 5.8 Hz), 7.643 (1H, dt, J=2.8 Hz), 8.455 (1H, dd,        J=2.5 Hz), 8.617 (1H, dd, J=1.2 Hz).

Embodiment 27

-   -   The method of Embodiment 25, wherein said oil and co-solvent        mixture is selected from the group consisting of 90% castor        oil/10% benzyl alcohol and 90% corn oil/10% benzyl alcohol.

Embodiment 28

-   -   A compound of Formula I, or a pharmaceutically acceptable salt        thereof,

-   -   -   wherein R¹ is R¹⁰, O—R¹⁰, or NHR¹⁰        -   wherein R¹⁰ is selected from:        -   a C₇₋₃₀ alkyl; a C₇₋₃₀ alkenyl; a C₇₋₃₀ alkynyl; an alkyl            substituted with a cycloalkyl, which has a total number of            carbons between 5 and 16; an alkyl substituted with a            phenyl, which has a total number of carbons between 7 and            16; a cycloalkyl optionally substituted with one or more            alkyl, which has a total number of carbons between 5 and 16;            and

Embodiment 29

-   -   The compound of Embodiment 28, or a pharmaceutically acceptable        salt thereof, wherein R¹⁰ is a C₇₋₁₆ alkyl.

Embodiment 30

-   -   The compound of Embodiment 28, or a pharmaceutically acceptable        salt thereof, wherein R¹⁰ is an alkyl substituted with a C₃₋₆        cycloalkyl, which has a total number of carbons between 6 and        12.

Embodiment 31

-   -   The compound of Embodiment 28, or a pharmaceutically acceptable        salt thereof, wherein R¹ is a C₇₋₁₆ alkyl.

Embodiment 32

-   -   The compound of Embodiment 28, or a pharmaceutically acceptable        salt thereof, wherein R¹ is an alkyl having the formula        —(CH₂)_(n)—CH₃, wherein n is an integer between 6 and 12, such        as 6, 7, 8, 9, 10, 11, or 12.

Embodiment 33

-   -   The compound of Embodiment 28, or a pharmaceutically acceptable        salt thereof, wherein R¹ is represented by the formula        —(CH₂)_(n)-Cy, wherein n is an integer of 1-6, and Cy is a C₃₋₆        cycloalkyl or phenyl.

Embodiment 34

-   -   The compound of Embodiment 33, or a pharmaceutically acceptable        salt thereof, wherein n is 1 or 2 and Cy is cyclopentyl,        cyclohexyl, or phenyl.

Embodiment 35

-   -   The compound of Embodiment 28, or a pharmaceutically acceptable        salt thereof, wherein R¹ is

Embodiment 36

The compound of Embodiment 28, or a pharmaceutically acceptable saltthereof, wherein R¹ is

or

Embodiment 37

-   -   A pharmaceutical composition comprising the compound of any one        of Embodiments 28-36, or a pharmaceutically acceptable salt        thereof.

Embodiment 38

-   -   The pharmaceutical composition of Embodiment 37, formulated for        parenteral administration.

Embodiment 39

-   -   The pharmaceutical composition of Embodiment 38, formulated for        intramuscular injection, intradermal injection, or subcutaneous        injection.

Embodiment 40

-   -   The pharmaceutical composition of Embodiment 37, further        comprising a pharmaceutically acceptable carrier.

Embodiment 41

-   -   The pharmaceutical composition of Embodiment 40, wherein the        pharmaceutically acceptable carrier comprises a pharmaceutically        acceptable oil, e.g., an oil suitable for use as vehicles for        injection, such as an oil of vegetable origin or synthetic mono-        or di-glycerides of fatty acids, e.g., a vegetable oil, castor        oil, corn oil, sesame oil, cottonseed oil, peanut oil, poppy        seed oil, tea seed oil, or soybean oil.

Embodiment 42

-   -   The pharmaceutical composition of Embodiment 40 or 41, further        comprising a pharmaceutically acceptable solvent, e.g., benzyl        alcohol.

Embodiment 43

-   -   The pharmaceutical composition of any one of Embodiments 37-42,        which is a non-aqueous solution or suspension.

Embodiment 44

-   -   A pharmaceutical composition comprising a compound of Formula        II, or a pharmaceutically acceptable salt thereof,

-   -   -   wherein R² is R²⁰, OR²⁰, or NHR²⁰,        -   wherein R²⁰ is selected from:        -   a C₁₋₃₀ alkyl; a C₂₋₃₀ alkenyl; a C₂₋₃₀ alkynyl; an alkyl            substituted with a cycloalkyl, which has a total number of            carbons between 4 and 30; an alkyl substituted with a            phenyl, which has a total number of carbons between 7 and            30; and a cycloalkyl optionally substituted with one or more            alkyl, which has a total number of carbons between 3 and 30,        -   wherein the pharmaceutical composition is formulated for            intramuscular injection, intradermal injection, or            subcutaneous injection, and the compound of Formula II or            pharmaceutically acceptable salt thereof is present in the            pharmaceutical composition at a concentration of about 25            mg/ml to about 500 mg/ml.

Embodiment 45

-   -   The pharmaceutical composition of Embodiment 44, wherein R² in        Formula II is selected from a C₁₋₁₆ alkyl; an alkyl substituted        with a cycloalkyl, which has a total number of carbons between 5        and 16; an alkyl substituted with a phenyl, which has a total        number of carbons between 7 and 16; and a cycloalkyl optionally        substituted with one or more alkyl, which has a total number of        carbons between 5 and 16.

Embodiment 46

-   -   The pharmaceutical composition of Embodiment 44, wherein R² in        Formula II is an alkyl having the formula —(CH₂)_(n)—CH₃,        wherein n is an integer between 0 and 12.

Embodiment 47

-   -   The pharmaceutical composition of Embodiment 44, wherein R² in        Formula II is represented by the formula —(CH₂)_(n)-Cy, wherein        n is an integer of 1-6, and Cy is a C₃₋₆ cycloalkyl or phenyl.

Embodiment 48

-   -   The pharmaceutical composition of Embodiment 44, wherein R² in        Formula II is

or

Embodiment 49

-   -   The pharmaceutical composition of any one of Embodiments 44-48,        which is a non-aqueous solution or suspension.

Embodiment 50

-   -   The pharmaceutical composition of any one of Embodiments 44-49,        wherein the compound of Formula II or pharmaceutically        acceptable salt thereof is dissolved or suspended in a        pharmaceutically acceptable oil, e.g., an oil suitable for use        as vehicles for injection, such as an oil of vegetable origin or        synthetic mono- or di-glycerides of fatty acids, e.g., a        vegetable oil, castor oil, corn oil, sesame oil, cottonseed oil,        peanut oil, poppy seed oil, tea seed oil, or soybean oil.

Embodiment 51

-   -   The pharmaceutical composition of any one of Embodiments 44-50,        further comprising a pharmaceutically acceptable solvent, e.g.,        benzyl alcohol.

Embodiment 52

-   -   The pharmaceutical composition of any one of Embodiments 44-51,        which comprises the compound of Formula II or pharmaceutically        acceptable salt thereof in an amount sufficient to provide a        therapeutically effective blood plasma concentration of        abiraterone for a period of at least two weeks, after a single        administration to a subject having a hormone-dependent benign or        malignant disorder (e.g., metastatic castration resistant        prostate cancer or metastatic castration sensitive prostate        cancer).

Embodiment 53

-   -   The pharmaceutical composition of Embodiment 52, wherein the        therapeutically effective blood plasma concentration of        abiraterone is about 1 ng/ml or higher.

Embodiment 54

-   -   The pharmaceutical composition of Embodiment 53, wherein the        therapeutically effective blood plasma concentration of        abiraterone is about 8 ng/ml or higher.

Embodiment 55

-   -   A method of treating a hormone-dependent benign or malignant        disorder comprising administering to a subject in need thereof a        therapeutically effective amount of the compound of any one of        Embodiments 28-36 or a pharmaceutically acceptable salt thereof,        or the pharmaceutical composition of any one of Embodiments        37-54.

Embodiment 56

-   -   The method of Embodiment 55, wherein the administering is an        intramuscular injection, intradermal injection, or subcutaneous        injection.

Embodiment 57

-   -   The method of Embodiment 55 or 56, wherein the administering is        carried out without regard to whether the subject has food,        i.e., the compound or pharmaceutical composition is administered        with or without food.

Embodiment 58

-   -   The method of any one of Embodiments 55-57, wherein the        hormone-dependent benign or malignant disorder is prostate        cancer or breast cancer.

Embodiment 59

-   -   The method of any one of Embodiments 55-57, wherein the        hormone-dependent benign or malignant disorder is castration        resistant prostate cancer or castration sensitive prostate        cancer.

Embodiment 60

-   -   The method of any one of Embodiments 55-57, wherein the        hormone-dependent benign or malignant disorder is metastatic        castration resistant prostate cancer or metastatic castration        sensitive prostate cancer.

Embodiment 61

-   -   The method of any one of Embodiments 55-60, wherein the subject        is treated with a gonadotropin-releasing hormone analog and/or        bilateral orchiectomy.

Embodiment 62

-   -   The method of any one of Embodiments 55-61, further comprising        administering to the subject an effective amount of prednisone        or prednisolone.

Embodiment 63

-   -   The method of any one of Embodiments 55-62, wherein the        pharmaceutical composition is administered to the subject once a        week or once in more than a week, e.g., the dosing frequency        ranges from once a week to once every few months, such as from        once a week to once every eight weeks, or once a week to once        every three months.

Embodiment 64

-   -   The method of any one of Embodiments 55-63, wherein the        administering provides a blood plasma concentration of        abiraterone above 1.0 ng/ml for a period of at least two weeks.

Embodiment 65

-   -   The method of any one of Embodiments 55-63, wherein the        administering provides a blood plasma concentration of        abiraterone above 8.4 ng/ml for a period of at least two weeks.

Embodiment 66

-   -   The method of any one of Embodiments 55-65, wherein the        administering provides a single dose or steady state C_(max) of        abiraterone between about 10 ng/ml and about 400 ng/ml (e.g.,        between about 50 ng/ml and about 100 ng/ml, or between about 15        ng/ml and about 160 ng/ml).

Provided herein are formulations, methods, and kits for treating asubject with a sex hormone-dependent benign or malignant disorder suchas prostate cancer. Also provided are methods for preparing theformulations useful for treating a subject with a sex hormone-dependentbenign or malignant disorder (such as prostate cancer), a syndrome dueto androgen excess, and/or a syndrome due to glucocorticoid excess suchas hypercortisolemia. Reference will now be made in detail torepresentative embodiments, examples of which are illustrated in theaccompanying drawings.

The term “subject” as used herein means, but is not limited to, ananimal or human in need of or capable of receiving chemotherapy for asex hormone-dependent benign or malignant disorder such as, for example,an androgen-dependent disorder or an estrogen-dependent disorder(including prostate cancer and breast cancer), an animal or human inneed of or capable of receiving therapy for non-oncologic syndromes dueto androgen excess, such as endometriosis, polycystic ovary syndrome,congenital adrenal hyperplasia (e.g., classical or nonclassicalcongenital adrenal hyperplasia), precocious puberty, hirsutism, etc.,and/or due to glucocorticoid excess such as hypercortisolemia, such asCushing's syndrome or Cushing's disease. In preferred embodiments, thesubject is a human subject.

The term “other drug or agent” as used herein (when, for example,referring to prior, simultaneous, and post-administration of at leastone other drug or agent with at least one abiraterone prodrugformulation) means at least one other compound, formulation, molecule,biologic, or the like, capable of enhancing the efficacy of theformulation(s), decreasing an undesirable side effect(s) of theformulation(s), or improving the treatment of the particular disorder.Any suitable routes of administration of such “other drug or agent” canbe used, for example, oral administration, parenteral administration,etc. A person skilled in the art of treating a subject having a sexhormone-dependent benign or malignant disorder (such as anandrogen-dependent disorder or an estrogen-dependent disorder),syndromes due to androgen excess syndrome, and/or syndromes due toglucocorticoid excess such as hypercortisolemia would know andunderstand how to choose and use such “other drug or agent” for theintended purpose(s).

The formulations can optionally be administered via a modified-releasedevice or method. The term “modified-release” as used herein should beunderstood as encompassing delayed release, prolonged or extendedrelease, sustained release, or a targeted release, etc. For example, insome embodiments, the modified release device or method can furtherprolong the release of abiraterone of the prodrugs and formulations ofthe present disclosure. In some embodiments, the modified release deviceor method can also include any device or method capable of releasing anagent or product (for example, a drug or a biologic) at a time laterthan immediately following its administration (and can include, forexample, implants). Various modified release devices have been described(Stubbe et al., Pharm. Res. 21:1732, 2004) and could be applicable tothe representative embodiments. Modified-release devices and methods canbe identified and employed without undue experimentation by a personskilled in the art after consideration of all criteria and use of bestjudgment on the subject's behalf.

The formulations and agents of the embodiments are administered in apharmacologically or physiologically acceptable and effective amount toreduce or eliminate the presence, for example, of prostate tumor tissueand abnormal or malignant prostate cells in a subject presenting withprostate cancer. Similarly, the formulations and agents of theembodiments are administered alone or in combination with othertherapeutic agents or therapeutic modalities (for example, radiotherapyand surgery) in prophylactically or therapeutically effective amounts,which are to be understood as amounts meeting the intended prophylacticor therapeutic objectives, and providing the benefits available fromadministration of such formulations and agents.

The terms “effective amount,” “effective dose,” and “therapeutic bloodplasma concentration” as used herein mean, but are not limited to, anamount, dose, or concentration capable of treating, delaying, slowing,inhibiting or eliminating the onset, existence or progression of adisorder, disease or condition. For example, an “effective amount,”“effective dose,” or “therapeutic blood plasma concentration” is capableof reducing or eliminating the presence of prostate tumor tissue andabnormal or malignant prostate cells in a subject presenting withprostate cancer, which is sufficient to cure (partly or completely)illness or prevent the onset or further spread of disorder, disease orcondition. For further example, an effective amount of formulationrefers to the amount administered alone or in combination with othertherapeutic agents or therapeutic modalities (for example, radiotherapyand surgery) to achieve clinically-significant reduction in tumorburden. A person skilled in the art would understand when aclinically-significant reduction in tumor burden (or improvement of asex hormone-dependent benign or malignant disorder or another disorderor syndrome described herein) has occurred following administration of aformulation. An “effective amount,” “effective dose,” or “therapeuticblood plasma concentration” is understood to be an amount, dose, orconcentration not critically harmful to the subject and, in any case,where any harmful side effects are outweighed by benefits. By way ofexample only, an effective amount or dose of an abiraterone prodrugformulation means an amount capable of attaining blood plasmaconcentrations of at least 1 ng/ml, e.g., at least 1 ng/ml, at least 2ng/ml, at least 4 ng/ml, or at least 8 ng/ml, of abiraterone in thesubject following parenteral administration of the prodrug formulation,and the efficacious blood plasma concentrations are attained for atleast one week, e.g., at least two weeks (for example, four, six, eightor more weeks) following administration.

In general, the dosage ranges for administration of the formulationaccording to the present disclosure are those that produce the desiredeffect(s). The useful dosage to be administered will vary depending onthe age, weight, and health of the subject treated, the mode, route, andschedule of administration, the response of the individual subject, andthe type or staging of prostate cancer (or severity of a sexhormone-dependent benign or malignant disorder or another syndrome ordisorder described herein) against which treatment with the formulationis sought. The dosage will also vary with the nature or the severity ofthe primary tumor and other underlying conditions, with epidemiologicconditions, with the concomitant use of other active compounds, and theroute of administration. In addition, the dosage will be determined bythe existence of any adverse side effects such as localhypersensitivity, systemic adverse effects, and immune tolerance.

An effective dose of the formulations (and other agent(s)) can bedetermined without undue experimentation (for example, bypharmacokinetic studies) by a person skilled in the art afterconsideration of all criteria and use of best judgment on the patient'sbehalf (and will most often be contingent upon the particularformulation utilized). The dosage to be administered will depend uponthe particular case, but in any event, it is the amount sufficient toinduce clinical benefit against, or improvement of, a sexhormone-dependent benign or malignant disorder (such as prostatecancer), a syndrome due to androgen excess, and/or a syndrome due toglucocorticoid excess such as hypercortisolemia.

The formulations and agents of the embodiments can, optionally, beadministered in combination with (or can include) one or morepharmaceutically acceptable carriers, diluents, or excipients.Formulations, administration techniques, pharmaceutical compositions,methods of preparing pharmaceutical compositions, and pharmaceuticallyacceptable carriers, diluents, and excipients are known in the art andare described, for example, in “Remington: The Science and Practice ofPharmacy” (formerly “Remington's Pharmaceutical Sciences,” University ofthe Sciences in Philadelphia, Lippincott, Williams & Wilkins,Philadelphia, Pa. (2005)), the disclosure of which is herebyincorporated by reference. A person skilled in the art can use knowninjectable, physiologically acceptable sterile solutions. For preparinga ready-to-use solution for parenteral injection or infusion, aqueousisotonic solutions, for example, saline, phosphate buffered saline (PBS)or corresponding plasma protein solutions, are readily available. Theformulations can be present as lyophilisates or dry preparations, whichcan be reconstituted with a known injectable solution directly beforeuse under sterile conditions, for example, as a kit of parts. Inaddition, the formulations can include one or more acceptable carriers(which can include, for example, solvents, dispersion media, coatings,adjuvants, stabilizing agents, diluents, preservatives, antibacterialand antifungal agents, isotonic agents, absorption-modifying agents, andthe like. “Diluents” can include water, saline, phosphate-bufferedsaline (PBS), dextrose, ethanol, glycerol, and the like. Isotonic agentscan include sodium chloride, dextrose, mannitol, sorbitol, and lactose,among others. Stabilizers include albumin and alkali salts ofethylenediaminetetraacetic acid, among others.

Any suitable route of administration can be employed for providing asubject with an effective amount/dosage of formulation and agentsaccording to the representative embodiments. A suitable route ofadministration can be determined readily by a person skilled in the artof pharmacology, immunology, medicine, oncology, or the like withoutundue experimentation. However, it is anticipated that the formulationsare primarily suitable for parenteral administration such as via IMinjection, intradermal injection, or subcutaneous injection.

The abbreviations used herein have their conventional meaning within thechemical and biological arts.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987. The disclosure is not intended to belimited in any manner by the exemplary listing of substituents describedherein.

As used herein, the term “alkyl” as used by itself or as part of anothergroup refers to a straight- or branched-chain saturated aliphatichydrocarbon. In some embodiments, the alkyl can include one to thirtycarbon atoms (i.e., C₁₋₃₀ alkyl or alternatively expressed as C₁-C₃₀alkyl) or the number of carbon atoms designated (i.e., a C₁ alkyl suchas methyl, a C₂ alkyl such as ethyl, a C₃ alkyl such as propyl orisopropyl, etc.). In one embodiment, the alkyl group is a straight chainC₁₋₁₆ alkyl group. In another embodiment, the alkyl group is a branchedchain C₃₋₁₆ alkyl group.

As used herein, the term “cycloalkyl” as used by itself or as part ofanother group refers to saturated and partially unsaturated (e.g.,containing one or two double bonds) cyclic aliphatic hydrocarbonscontaining one to three rings having from three to twelve carbon atoms(i.e., C₃₋₁₂ cycloalkyl) or the number of carbons designated. In oneembodiment, the cycloalkyl group has two rings. In one embodiment, thecycloalkyl group has one ring. In another embodiment, the cycloalkylgroup is a C₃₋₈ cycloalkyl group. In another embodiment, the cycloalkylgroup is a C₃₋₆ cycloalkyl group. “Cycloalkyl” also includes ringsystems wherein the cycloalkyl ring, as defined above, is fused with oneor more aryl or heteroaryl groups wherein the point of attachment is onthe cycloalkyl ring, and in such instances, the number of carbonscontinue to designate the number of carbons in the cycloalkyl ringsystem. Non-limiting exemplary cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl,decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

As used herein, the term “alkenyl” as used by itself or as part ofanother group refers to a straight- or branched-chain aliphatichydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbondouble bonds. In one embodiment, the alkenyl group is a C₂₋₁₆ alkenylgroup.

As used herein, the term “alkynyl” as used by itself or as part ofanother group refers to a straight- or branched-chain aliphatichydrocarbon containing one or more (e.g., 1, 2, or 3) carbon-to-carbontriple bonds. In one embodiment, the alkynyl has one carbon-carbontriple bond. In one embodiment, the alkynyl group is a C₂₋₁₆ alkynylgroup.

As used herein, the term “abiraterone prodrug(s) of the presentdisclosure” refers to any of the compounds described herein according toFormula I or II, a lipophilic ester of abiraterone prodrug, or any ofExample Nos. 2A-2H, isotopically labeled compound(s) thereof (e.g.,deuterium enriched compounds), possible stereoisomers thereof (includingdiastereoisomers, enantiomers, and racemic mixtures), tautomers thereof,conformational isomers thereof, and/or pharmaceutically acceptable saltsthereof (e.g., acid addition salt such as HCl salt). Hydrates andsolvates of the prodrugs of the present disclosure are consideredcompositions of the present disclosure, wherein the prodrug(s) is inassociation with water or solvent, respectively. Some of the prodrugs ofthe present disclosure can also exist in various polymorphic forms oramorphous forms. The prodrugs described herein include those compoundsthat readily undergo chemical changes under physiological conditions toprovide active abiraterone. Additionally, prodrugs can be converted bychemical or biochemical methods in an ex vivo environment. As usedherein, the term “abiraterone prodrug formulation(s) of the presentdisclosure” refers to any of the pharmaceutical composition orformulation comprising any one or more of the abiraterone prodrugs ofthe present disclosure, for example, any of the formulations prepared inExamples 3A-3J. In any of the embodiments described herein, unlessdirectly contradictory from context, the abiraterone prodrug of thepresent disclosure can be abiraterone decanoate. In any of theembodiments described herein, unless directly contradictory fromcontext, the abiraterone prodrug formulation of the present disclosurecan be any of the pharmaceutical composition comprising abirateronedecanoate as described herein. In any of the embodiments describedherein, unless directly contradictory from context, the abirateroneprodrug of the present disclosure can also be abiraterone isocaproate.In any of the embodiments described herein, unless directlycontradictory from context, the abiraterone prodrug formulation of thepresent disclosure can also be any of the pharmaceutical compositioncomprising abiraterone isocaproate as described herein.

The abiraterone prodrugs of the present disclosure can exist inisotope-labeled or -enriched form containing one or more atoms having anatomic mass or mass number different from the atomic mass or mass numbermost abundantly found in nature. Isotopes can be radioactive ornon-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon,oxygen, and nitrogen, include, but are not limited to ²H, ³H, ¹³C, ¹⁴C,¹⁵N, and ¹⁸O. Compounds that contain other isotopes of these and/orother atoms are within the scope of this disclosure.

Solid and dashed wedge bonds indicate stereochemistry as customary inthe art.

The following examples are provided for illustration purposes only, andare in no way intended to limit the scope of the claimed subject matter.

Example 1 Long-Acting Injectable Formulations of Abiraterone Prodrugs

The formulations include long acting injectable oil-based formulationsof a lipophilic abiraterone prodrug such as (1) abiraterone3β-alkanoates and (2) linear, branched, cyclic, and aromatic alkanoatesof C-2 to C-16 carbons (that is, aliphatic and aromatic esters made of 2to 16 carbon atoms). The abiraterone esters can include, for example,the following esters: an acetate, a propionate, a butanoate, a(vaterate) pentanoate, an isocaproate, a buciclate, acyclohexanecarboxylate, a phenyl propionate, caproate (hexanoate), aenanthate (heptanoate), a cypionate, an octanoate, a noncanoate, adecanoate, an undecanoate, a dodecanoate, a tridecanoate, atetradecanoate, a pentadecanoates, and a hexadecanoate. Inrepresentative embodiments, the abiraterone esters are abirateroneacetate, abiraterone propionate, and abiraterone decanoate.

The formulations can comprise a solution or suspension of abirateroneprodrug in pharmaceutically acceptable oils, such as pharmaceuticallyacceptable oils for injection, including oils of vegetable origin orsynthetic mono- or diglycerides of fatty acids. In some embodiments,pharmaceutically acceptable oils can include triglycerides made up offatty acids (poly-unsaturated, mono-unsaturated, and saturated) such asthe following: vegetable oil, castor oil, corn oil, sesame oil,cottonseed oil, peanut oil (arachis oil), poppy seed oil, tea seed oil,and soybean oil. Vegetable oils were selected based on the solubility ofthe prodrug in the oil. It was determined that abiraterone acetate wasmost soluble in castor oil, which includes a triglyceride, in which thefatty acid constituent is primarily rich in oleic acid (a hydroxylatedmonounsaturated fatty acid). Conversely, it was determined that the morelipophilic prodrugs (abiraterone propionate and abiraterone decanoate)were more soluble in corn oil, which includes a triglyceride, in whichthe fatty acid constituents are primarily linoleic acid(non-hydroxylated polyunsaturated fatty acid), oleic acid(non-hydroxylated unsaturated fatty acid), palmitic acid(non-hydroxylated saturated fatty acid), and stearic acid(non-hydroxylated saturated fatty acid). Surprisingly, it was determinedthat abiraterone butanoate has lower solubility in both castor oil andcorn oil than the acetate, propionate, or decanoate prodrugs. It wasalso noted that there is an inverse correlation between the meltingpoints and solubilities of the prodrugs in vegetable oils. The meltingpoints of the various abiraterone prodrugs were determined bydifferential scanning calorimetry as shown in Table 1.

TABLE 1 Melting Points of Abiraterone Prodrugs. Abiraterone ProdrugMelting point Acetate 127-130° C.    Propionate 102° C. Butanoate 147°C. Decanoate  38° C.

The formulations can contain pharmaceutically acceptable excipients suchas co-solvents (that is, solubilizing agents) such as benzyl alcohol,benzyl benzoate, ethanol, glycerol, polyethylene glycol, polysorbate 80,acetic acid, and ethyl acetate. It was determined that theadditives/co-solvents benzyl alcohol and benzyl benzoate had theadvantage of increasing the solubility of the prodrugs as well asreducing the viscosity and glide force of the solution, see e.g., FIGS.13A-13E and Tables 2A-2D, which provided a more concentrated solutionthat was easier to inject through an acceptable gauge needle for IMinjection (e.g., 20-27 gauge such as 22-25 gauge). Indeed, theco-solvent is selected based on its ability to reduce the viscosity ofthe vehicle to allow injection through suitable injection needles orcannula. Benzyl alcohol as an additive in IM or subcutaneous injectionsalso has the advantage that it can act as a local anesthetic at theinjection site (Wilson et al. Ann. Emer. Med. 33(5), 495, 1999).

The solubility of the abiraterone esters can be affected upon adding aco-solvent to the vegetable oil vehicle. Thus, in some embodiments, theabiraterone ester is completely dissolved in the composition, and inother embodiments the abiraterone ester is partly dispersed in thecomposition. In one embodiment, the abiraterone esters are fullydissolved in the vehicle.

The formulations can also contain pharmaceutically acceptablepreservatives, polymers, antioxidants, antimicrobials, chelating agents,and other excipients such as citric acid, dextrose, ascorbic acid,benzalkonium chloride, benzoic acid, sodium betadex sulfobutyl ether,calcium chloride, sodium carbomethoxycellulose, chlorobutanol, creatine,croscarmellose, dibasic potassium phosphate, sodium docusate, sodiumedetate, glycerin, sodium hyaluronate, hydroxypropyl betadex, lacticacid, lactose, lecithin, maleic acid, mannitol, meglumine,methylcellulose, methylparaben, microcrystalline cellulose, miripitiumchloride, momothioglycerol, phenol, poloxamer 188, polyglactin,polysorbate 20, polysorbate 40, polysorbate 80, propylparaben, sodiumacetate, sodium benzoate, sodium citrate, sorbitan monolaurate,sorbitol, sucrose, tartaric acid, trisodium citrate, tromantadine,tromethamine, and urea.

The formulations can be sterilized by methods known by persons skilledin the art (for example, gamma irradiation, micron filtration, andautoclaving).

The abiraterone prodrug formulations can be prepared at variousconcentrations including, for example, 25 mg/ml to 500 mg/ml. Inrepresentative embodiments the concentrations are 50 mg/ml to 300 mg/ml.

The formulations, following IM or subcutaneous injection, release aneffective amount of abiraterone over a period of at least one week andup to two, three, four, or more weeks. The therapeutic blood plasmalevels of abiraterone achieved following administration of theabiraterone prodrug formulations can be, for example, 6-15 ng/ml between14-28 days following parenteral administration. In representativeembodiments, the therapeutic levels are 8-12 ng/ml between 14-28 daysfollowing parenteral administration. It has been demonstrated that anabiraterone C_(min) of >8.4 ng/ml is associated with a favorableprostate-specific antigen response and could be a crucial predictivefactor for progression-free survival in castration resistant prostatecancer patients (Carton et al., Eur. J. Cancer, 72:54, 2017).

Example 2. Synthesis of Abiraterone Prodrugs

Abiraterone Acetate

Abiraterone acetate was obtained from Hetero Labs Limited, India.

Other abiraterone esters can be synthesized generally by reactingabiraterone with R²COOH or an appropriate activated form thereof, suchas R²COCl. The reaction is typically carried out in an aprotic solventsuch as CHCl₃ with an appropriate base such as triethyl amine. Examplesof preparation of abiraterone propionate, abiraterone butanoate,abiraterone pentanoate, abiraterone hexanoate, abiraterone heptanoate,abiraterone isocaproate, abiraterone cypionate, and abirateronedecanoate are shown below.

Example 2A. Preparation of Abiraterone Propionate

Abiraterone propionate was prepared as follows:

15.0 g (42.9 mmol) of abiraterone was added to a 500 ml round-bottomflask followed by 450 ml of chloroform and 11.96 ml (85.8 mmol, 2.0equiv) of triethylamine. The flask was purged with nitrogen and themixture was cooled to 0° C. in an ice bath. After stirring the mixturefor 15 minutes, 4.12 ml (47.2 mmol, 1.1 equiv) of propanoyl chloridewere added dropwise followed by addition of an additional 6.57 ml (47.2mmol, 1.1 equiv) of triethylamine. The ice bath was removed, and thesolution was stirred for an additional 2 hours. The reaction was onceagain cooled to 0° C., and an additional 4.12 ml of propanoyl chlorideand 6.57 mL of triethylamine were added slowly. The ice bath was againremoved, and the reaction stirred for another 16 hours. The solution wasthen washed twice with 300 ml of water and once with 300 ml of brine.The organic phase was dried over sodium sulfate, concentrated undervacuum, and loaded onto silica. The crude compound was purified by flashchromatography using an ethyl acetate/hexane solvent system. The desiredcompound was eluted with approximately 30% ethyl acetate. The purefractions were combined and concentrated under vacuum to provide 8.2 gof abiraterone propionate as a yellow solid, which was 97.8% pureaccording to HPLC analysis. Other chemical properties were as follows:LCMS m/z 406.3 (M+H); ¹H NMR (CDCl₃, 200 MHz): δ_(H) 1.096 (11H, m),1.625 (11H, m), 1.846 (3H, m), 2.067 (3H, m), 2.323 (5H, m), 4.627 (1H,m), 5.415 (1H, d, J=5 Hz), 5.992 (1H, q, J=5 Hz), 7.215 (1H, ddd, J=1,5.8 Hz), 7.677 (1H, dt, J=2.8 Hz), 8.456 (1H, dd, J=2.5 Hz), 8.619 (1H,dd, J=1.2 Hz); melting point (DSC) 101° C.

Example 2B. Preparation of Abiraterone Butanoate

Abiraterone butanoate was prepared as follows:

7.0 g (20.0 mmol) of abiraterone was added to a 500 ml round-bottomflask followed by 210 ml of chloroform and 5.58 ml (40.0 mmol, 2.0equiv) of triethylamine. The flask was purged with nitrogen and themixture was cooled to 0° C. in an ice bath. After stirring the mixturefor 15 minutes, 2.28 ml (22.0 mmol, 1.1 equiv) of butanoyl chloride wereadded dropwise followed by addition of an additional 3.07 ml (22.0 mmol,1.1 equiv) of triethylamine. The ice bath was removed, and the solutionwas stirred for an additional 2 hours. The reaction was once againcooled to 0° C., and an additional 2.28 ml of butanoyl chloride and 3.07mL of triethylamine were added slowly. The ice bath was again removed,and the reaction stirred for another 16 hours. During the course of thereaction, the color changed quickly from a white mixture to a yellowsolution and then slowly to a red solution. After confirmation by TLCand LCMS that the reaction was complete, the solution was then washedtwice with 150 ml of water and once with 150 ml of brine. The organicphase was dried over sodium sulfate, concentrated under vacuum, andloaded onto silica. The crude compound was purified by flashchromatography using an ethyl acetate/hexane solvent system. The desiredcompound was eluted with approximately 25% ethyl acetate. The purefractions were combined and concentrated under vacuum to provide 5.5 gof abiraterone butanoate as a yellow solid. Chemical properties were asfollows: LCMS m/z 420.4 (M+H); ¹H NMR (CDCl₃, 200 MHz): δH 0.948 (3H, t,J=7 Hz), 1.043 (3H, s), 1.090 (3H, s), 1.633 (15H, m), 1.842 (3H, m),2.065 (3H, m), 2.297 (5H, m), 4.608 (1H, m), 5.413 (1H, d, J=5 Hz),5.990 (1H, q, J=5 Hz), 7.215 (1H, ddd, J=1, 5.8 Hz), 7.643 (1H, dt,J=2.8 Hz), 8.455 (1H, dd, J=2.5 Hz), 8.615 (1H, dd, J=1.2 Hz); meltingpoint (DSC) 147° C.

Example 2C. Preparation of Abiraterone Decanoate

Abiraterone decanoate was prepared as follows:

10.0 g (28.6 mmol) of abiraterone was added to a 500 ml round-bottomflask followed by 300 ml of chloroform and 7.97 ml (57.2 mmol, 2.0equiv) of triethylamine. The flask was purged with nitrogen and themixture was cooled to 0° C. in an ice bath. After stirring the mixturefor 15 minutes, 6.53 ml (31.5 mmol, 1.1 equiv) of decanoyl chloride wereadded dropwise followed by addition of an additional 4.39 ml (31.5 mmol,1.1 equiv) of triethylamine. The ice bath was removed, and the solutionwas stirred for an additional 2 hours. The reaction was once againcooled to 0° C., and an additional 6.53 ml of decanoyl chloride and 4.39mL of triethylamine were added slowly. The ice bath was again removed,and the reaction stirred for another 16 hours. During the course of thereaction, the color changed quickly from a white mixture to a yellowsolution and then slowly to a red solution. After confirmation by TLCand LCMS that the reaction was complete, the solution was then washedtwice with 200 ml of water and once with 200 ml of brine. The organicphase was dried over sodium sulfate, concentrated under vacuum, andloaded onto silica. The crude compound was purified by flashchromatography using an ethyl acetate/hexane solvent system. The desiredcompound was eluted with approximately 20% ethyl acetate. The purefractions were combined and concentrated under vacuum to provide 8.0 gof abiraterone decanoate as a yellow solid. Chemical properties were asfollows: LCMS m/z 504.4 (M+H); ¹H NMR (CDCl₃, 200 MHz): δH 0.877 (3H, t,J=7 Hz), 1.043 (3H, s), 1.082 (3H, s), 1.268 (16H, m), 1.643 (15H, m),1.842 (3H, m), 2.065 (3H, m), 2.290 (5H, m), 4.602 (1H, m), 5.404 (1H,d, J=5 Hz), 5.998 (1H, q, J=5 Hz), 7.215 (1H, ddd, J=1, 5.8 Hz), 7.643(1H, dt, J=2.8 Hz), 8.455 (1H, dd, J=2.5 Hz), 8.617 (1H, dd, J=1.2 Hz);melting point (DSC) 38° C.

Example 2D. Preparation of Abiraterone Pentanoate

Abiraterone pentanoate was prepared using a procedure similar to theprocedure for preparing abiraterone decanoate (Example 2C), except thatvaleroyl chloride was used instead of decanoyl chloride. LCMS m/z 434.3(M+H); ¹H NMR (CDCl₃, 200 MHz): δ_(H) 0.9-2.2 (32H, m), 4.61 (1H, m),5.41 (1H, d, J=5 Hz), 5.99 (1H, q, J=5 Hz), 7.22 (1H, ddd, J=1, 5.8 Hz),7.63 (1H, dt, J=2.8 Hz), 8.45 (1H, dd, J=2.5 Hz), 8.62 (1H, dd, J=1.2Hz).

Example 2E. Preparation of Abiraterone Hexanoate

Abiraterone hexanoate was prepared using a procedure similar to theprocedure for preparing abiraterone decanoate (Example 2C), except thathexanoyl chloride was used instead of decanoyl chloride. LCMS m/z 448.4(M+H); ¹H NMR (CDCl₃, 200 MHz): δ_(H) 0.9-2.2 (34H, m), 4.60 (1H, m),5.40 (1H, d, J=5 Hz), 5.98 (1H, q, J=5 Hz), 7.21 (1H, ddd, J=1, 5.8 Hz),7.62 (1H, dt, J=2.8 Hz), 8.43 (1H, dd, J=2.5 Hz), 8.60 (1H, dd, J=1.2Hz).

Example 2F. Preparation of Abiraterone Heptanoate

Abiraterone heptanoate was prepared using a procedure similar to theprocedure for preparing abiraterone decanoate (Example 2C), except thatheptanoyl chloride was used instead of decanoyl chloride. LCMS m/z 462.4(M+H); ¹H NMR (CDCl₃, 200 MHz): δ_(H) 0.9-2.2 (36H, m), 4.61 (1H, m),5.40 (1H, d, J=5 Hz), 6.00 (1H, q, J=5 Hz), 7.21 (1H, ddd, J=1, 5.8 Hz),7.64 (1H, dt, J=2.8 Hz), 8.45 (1H, dd, J=2.5 Hz), 8.61 (1H, dd, J=1.2Hz).

Example 2G. Preparation of Abiraterone Isocaproate

Abiraterone isocaproate was prepared using a procedure similar to theprocedure for preparing abiraterone decanoate (Example 2C), except that4-methylvaleryl chloride was used instead of decanoyl chloride. LCMS m/z448.4 (M+H); ¹H NMR (CDCl₃, 200 MHz): δ_(H) 0.9-2.2 (34H, m), 4.61 (1H,m), 5.40 (1H, d, J=5 Hz), 6.00 (1H, q, J=5 Hz), 7.22 (1H, ddd, J=1, 5.8Hz), 7.64 (1H, dt, J=2.8 Hz), 8.45 (1H, dd, J=2.5 Hz), 8.62 (1H, dd,J=1.2 Hz).

Example 2H. Preparation of Abiraterone Cypionate

Abiraterone cypionate was prepared using a procedure similar to theprocedure for preparing abiraterone decanoate (Example 2C), except that3-cyclopentylpropanoyl chloride was used instead of decanoyl chloride.LCMS m/z 474.4 (M+H); ¹H NMR (CDCl₃, 200 MHz): δ_(H) ¹H NMR (CDCl₃, 200MHz): δ_(H) 0.9-2.3 (36H, m), 4.62 (1H, m), 5.41 (1H, d, J=5 Hz), 6.00(1H, q, J=5 Hz), 7.22 (1H, ddd, J=1, 5.8 Hz), 7.63 (1H, dt, J=2.8 Hz),8.45 (1H, dd, J=2.5 Hz), 8.62 (1H, dd, J=1.2 Hz).

Example 3. Preparation of Formulations of Abiraterone Prodrugs Example3A. Preparation of Abiraterone Acetate Castor Oil Solution

An abiraterone acetate injectable (IM depot) castor oil solution wasprepared as follows:

490 mg of abiraterone acetate was weighed and placed in a 10-mL serumvial with a crimped stopper. 8 mL of castor oil was placed in a separate10-mL serum vial with a crimped stopper. The two vials were then wrappedin aluminum foil and sterilized in an autoclave using a 30-minute liquidcycle. Following sterilization, the vials were moved to a laminar flowhood. Then, 7 mL of the sterile castor oil was removed and added to thesterile abiraterone acetate and the vial was re-stoppered and crimpedclosed. The abiraterone acetate was then dissolved by sonicating,vortexing, and placing the vials on a rotator. The final concentrationof the sterile solution of abiraterone acetate was 70 mg/ml.

Example 3B. Preparation of Abiraterone Acetate 90% Castor Oil, 10%Benzyl Alcohol Solution

An abiraterone acetate injectable (IM depot) 90% castor oil, 10% benzylalcohol solution was prepared as follows:

700 mg of abiraterone acetate was weighed and placed in a 10-mL serumvial with a crimped stopper. 8 mL of a 90% castor oil/10% benzyl alcoholmixture was placed in a separate 10-mL serum vial with a crimpedstopper. The two vials were then wrapped in aluminum foil and sterilizedin an autoclave using a 30-minute liquid cycle. Following sterilization,the vials were moved to a laminar flow hood. Then, 7 mL of the sterile90% castor oil/10% benzyl alcohol solution was removed and added to thesterile abiraterone acetate and the vial was re-stoppered and crimpedclosed. The abiraterone acetate was then dissolved by sonicating,vortexing, and placing the vials on a rotator. The final concentrationof the sterile solution of abiraterone acetate was 91 mg/ml.

Example 3C. Preparation of Abiraterone Acetate 50% Castor Oil, 50%Benzyl Benzoate Solution

An abiraterone acetate injectable (IM depot) 50% castor oil, 50% benzylbenzoate solution was prepared as follows:

980 mg of abiraterone acetate was weighed and placed in a 10-mL serumvial with a crimped stopper. 8 mL of a 50% castor oil/50% benzylbenzoate mixture was placed in a separate 10-mL serum vial with acrimped stopper. The two vials were then wrapped in aluminum foil andsterilized in an autoclave using a 30-minute liquid cycle. Followingsterilization, the vials were moved to a laminar flow hood. Then, 7 mLof the sterile 50% castor oil/50% benzyl benzoate mixture solution wasremoved and added to the sterile abiraterone acetate and the vial wasre-stoppered and crimped closed. The abiraterone acetate was thendissolved by sonicating, vortexing, and placing the vials on a rotator.The final concentration of the sterile solution of abiraterone acetatewas 124 mg/ml.

Example 3D. Preparation of Abiraterone Propionate 90% Castor Oil, 10%Benzyl Alcohol Solution

An abiraterone propionate injectable (IM depot) 90% castor oil, 10%benzyl alcohol solution was prepared as follows:

1,050 mg of abiraterone propionate was weighed and placed in a 10-mLserum vial with a crimped stopper. 8 mL of a 90% castor oil/10% benzylalcohol mixture was placed in a separate 10-mL serum vial with a crimpedstopper. The vehicle vial was then wrapped in aluminum foil andsterilized in an autoclave using a 30-minute liquid cycle. Followingsterilization, the vials were moved to a laminar flow hood. Then, 8 mLof the sterile 90% castor oil/10% benzyl alcohol solution was removedand added to the abiraterone propionate and the vial was re-stopperedand crimped closed. The abiraterone propionate was then dissolved bysonicating, vortexing, and placing the vials on a rotator. The finalconcentration of the sterile solution of abiraterone propionate was 197mg/ml.

Example 3E. Preparation of Abiraterone Propionate 90% Corn Oil, 10%Benzyl Alcohol Solution

An abiraterone propionate injectable (IM depot) 90% corn oil, 10% benzylalcohol solution was prepared as follows:

1,050 mg of abiraterone propionate was weighed and placed in a 10-mLserum vial with a crimped stopper. 8 mL of a 90% corn oil/10% benzylalcohol mixture was placed in a separate 10-mL serum vial with a crimpedstopper. The vehicle vial was then wrapped in aluminum foil andsterilized in an autoclave using a 30-minute liquid cycle. Followingsterilization, the vials were moved to a laminar flow hood. Then, 8 mLof the sterile 90% corn oil/10% benzyl alcohol solution was removed andadded to the abiraterone propionate and the vial was re-stoppered andcrimped closed. The abiraterone propionate was then dissolved bysonicating, vortexing, and placing the vials on a rotator. The finalconcentration of the sterile solution of abiraterone propionate was 168mg/ml.

Example 3F. Preparation of Abiraterone Decanoate 90% Castor Oil, 10%Benzyl Alcohol Solution

An abiraterone decanoate injectable (IM depot) 90% castor oil, 10%benzyl alcohol solution was prepared as follows:

1,260 mg of abiraterone decanoate was weighed and placed in a 10-mLserum vial with a crimped stopper. 8 mL of a 90% castor oil/10% benzylalcohol mixture was placed in a separate 10-mL serum vial with a crimpedstopper. The vehicle vial was then wrapped in aluminum foil andsterilized in an autoclave using a 30-minute liquid cycle. Followingsterilization, the vials were moved to a laminar flow hood. Then, 8 mLof the sterile 90% castor oil/10% benzyl alcohol solution was removedand added to the abiraterone decanoate and the vial was re-stoppered andcrimped closed. The abiraterone decanoate was then dissolved bysonicating, vortexing, and placing the vials on a rotator. The finalconcentration of the sterile solution of abiraterone decanoate was 160mg/ml.

Example 3G. Preparation of Abiraterone Decanoate 90% Corn Oil, 10%Benzyl Alcohol Solution

An abiraterone decanoate injectable (IM depot) 90% corn oil, 10% benzylalcohol solution was prepared as follows:

1,260 mg of abiraterone decanoate was weighed and placed in a 10-mLserum vial with a crimped stopper. 8 mL of a 90% corn oil/10% benzylalcohol mixture was placed in a separate 10-mL serum vial with a crimpedstopper. The vehicle vial was then wrapped in aluminum foil andsterilized in an autoclave using a 30-minute liquid cycle. Followingsterilization, the vials were moved to a laminar flow hood. Then, 8 mLof the sterile 90% corn oil/10% benzyl alcohol solution was removed andadded to the abiraterone decanoate and the vial was re-stoppered andcrimped closed. The abiraterone decanoate was then dissolved bysonicating, vortexing, and placing the vials on a rotator. The finalconcentration of the sterile solution of abiraterone decanoate was 170mg/ml.

Example 3H. Preparation of Abiraterone Decanoate (˜200 Mg/Ml) 70% CornOil, 10% Benzyl Alcohol, 20% Benzyl Benzoate Solution

An abiraterone decanoate injectable (IM depot ˜200 mg/ml) 70% corn oil,10% benzyl alcohol, 20% benzyl benzoate solution was prepared asfollows:

2,500 mg of abiraterone decanoate was weighed and placed in a 20-mLserum vial with a crimped stopper. 60 mL of a 70% corn oil/10% benzylalcohol/20% benzyl benzoate mixture was placed in a separate 100-mLserum vial with a crimped stopper. The vehicle vial was then wrapped inaluminum foil and sterilized in an autoclave using a 30-minute liquidcycle. Following sterilization, the vials were moved to a laminar flowhood. Then, 10 mL of the sterile 70% corn oil/10% benzyl alcohol/20%benzyl benzoate solution was removed and added to the abirateronedecanoate and the vial was re-stoppered and crimped closed. Theabiraterone decanoate was then dissolved by sonicating, vortexing, andplacing the vials on a rotator. The final concentration of the sterilesolution of abiraterone decanoate was 209 mg/ml.

Example 3I. Preparation of Abiraterone Decanoate (˜240 Mg/Ml) 70% CornOil, 10% Benzyl Alcohol, 20% Benzyl Benzoate Solution

An abiraterone decanoate injectable (IM depot ˜240 mg/ml) 70% corn oil,10% benzyl alcohol, 20% benzyl benzoate solution was prepared asfollows:

3,125 mg of abiraterone decanoate was weighed and placed in a 20-mLserum vial with a crimped stopper. 60 mL of a 70% corn oil/10% benzylalcohol/20% benzyl benzoate mixture was placed in a separate 100-mLserum vial with a crimped stopper. The vehicle vial was then wrapped inaluminum foil and sterilized in an autoclave using a 30-minute liquidcycle. Following sterilization, the vials were moved to a laminar flowhood. Then, 10 mL of the sterile 70% corn oil/10% benzyl alcohol/20%benzyl benzoate solution was removed and added to the abirateronedecanoate and the vial was re-stoppered and crimped closed. Theabiraterone decanoate was then dissolved by sonicating, vortexing, andplacing the vials on a rotator. The final concentration of the sterilesolution of abiraterone decanoate was 242 mg/ml.

Example 3J. Preparation of Abiraterone Isocaproate 90% Corn Oil, 10%Benzyl Alcohol Solution

An abiraterone isocaproate injectable (IM depot) 90% corn oil, 10%benzyl alcohol solution was prepared as follows:

1190 mg of abiraterone isocaproate was weighed and placed in a 10-mLserum vial with a crimped stopper. 8 mL of a 90% corn oil/10% benzylalcohol mixture was placed in a separate 10-mL serum vial with a crimpedstopper. The vehicle vial was then wrapped in aluminum foil andsterilized in an autoclave using a 30-minute liquid cycle. Followingsterilization, the vials were moved to a laminar flow hood. Then, 6.4 mLof the sterile 90% corn oil/10% benzyl alcohol solution was removed andadded to the abiraterone isocaproate and the vial was re-stoppered andcrimped closed. The abiraterone isocaproate was then dissolved bysonicating, vortexing, and placing the vials on a rotator. The finalconcentration of the sterile solution of abiraterone isocaproate was 158mg/ml.

Example 4A. Solubility Testing of Abiraterone Prodrugs

The solubilities of various abiraterone prodrugs were tested as follows.The results are shown in Table 2.

For each solvent studied, a sufficient quantity of prodrug was weighedinto a separate glass vial and 1-2 ml of solvent was added. Theresultant suspension was sonicated and vortexed. If the prodrug wascompletely dissolved, more prodrug was added until an excess of materialwas observed. If there was a large excess of undissolved prodrug,additional diluent could be added. The total mass and volume used wererecorded. Each vial was tightly capped and wrapped with foil to protectit from light as necessary. The vials were placed on a laboratoryrotator in a 25° C. incubator (or at any other temperature that wasrequired). The samples were allowed to equilibrate for a minimum of 1day before assessing solubility. A later second time point, typically atabout 1 week, was also taken to confirm the solubility of each prodrug.

At the appropriate time point, the vials were removed from theincubator. A small amount of supernatant from each vial was transferredinto a microcentrifuge tube containing a 0.22 or 0.45 um filter. Thetube was centrifuged at 10,000 rpm until all of the liquid passedthrough the filter to the bottom of the tube. Alternatively, sampleswere filtered using a 0.22 or 0.45 μm syringe filter. The filteredliquid was assayed using HPLC. Samples were diluted as necessary so thatthe sample concentrations were bracketed by the standards.

TABLE 2 Solubilities of Abiraterone Prodrugs. Abiraterone ProdrugSolubility (mg/ml) Vehicle Acetate Propionate Butanoate Decanoate Castoroil 74 154 36 188 Castor oil, 10% 112 188 52 190 benzyl alcohol Castoroil, 10% 91 — — — benzyl benzoate Castor oil, 50% 148 — — — benzylbenzoate Sesame oil 27 86 17 130 Cottonseed oil 27 85 17 152 Corn oil 56134 30 183 Corn oil, 10% — 223 — 277 benzyl alcohol Abiraterone ProdrugSolubility (mg/ml) Cypi- Iso- Hepta- Hexa- Penta- Vehicle onate caproatenoate noate noate Castor oil 48 120 124 173 89 Castor oil, 10% 108 160171 188 121 benzyl alcohol Corn oil 70 103 124 133 81 Corn oil, 10% 121183 189 204 146 benzyl alcohol

The parenteral formulations must be sterilized before administration.This can be achieved by a variety of techniques including heatsterilization (for example, dry heat or moist heat), radiationsterilization (for example, gamma ray sterilization), filtrationsterilization (for example, 0.22 micrometer membrane filters), orgaseous sterilization (for example, formaldehyde or ethylene oxide gas).

Example 4B. Solubility, Viscosity, and Glide Force Testings ofAbiraterone Decanoate Formulations or Oil Vehicles

This example tests properties of various abiraterone decanoateformulations and oil vehicles.

First, further solubility studies show solubility advantages ofabiraterone decanoate formulation 70% Corn oil, 10% benzyl alcohol, 20%benzyl Benzoate. See Table 2A below. The abiraterone decanoate used forthe studies in Table 2A was obtained from Example 6A.

TABLE 2A Solubility Studies of Abiraterone Decanoate in DifferentVehicles Equilibrium Formulation saturation solubility Corn Oil BenzylAlcohol Benzyl Benzoate (RT, mg/ml) 100%  — — 63 90% — 10% 79 80% — 20%94 95%  5% — 108 90% 10% — 170 85%  5% 10% 148 70% 10% 20% 240

As can be seen from this study, the combination of benzyl alcohol andbenzyl benzoate can significantly enhance the solubility of abirateronedecanoate in corn oil. See also FIGS. 13A and 13B.

Additional experiments also show that the inclusion of benzyl benzoatelowers viscosity and Glide Force of oil vehicles. It is expected thatsuch oil vehicles can be advantageously used in formulating theabiraterone prodrugs herein to provide a lower viscosity and lower GlideForce abiraterone prodrug formulation when desired.

The Glide Force testing was carried out with tensile and compressiontesting machine (e.g. Lloyd press or equivalent), NEXYGEN Plus materialstesting software, or equivalent Load cell 250N. 5-mL Luer-Lok Syringe(e.g. Becton, Dickinson and Company/BD, P/N 309646), or equivalent 23gauge, 1.5 inch length, thin wall, Precision Glide Needle (e.g. Becton,Dickinson and Company/BD, P/N 305194), or equivalent 27 gauge, 1.5 inchlength, regular wall, Precision Glide Needle (e.g. Becton, Dickinson andCompany/BD, P/N 301629), or equivalent.

Table 2B shows the viscosity of various oil vehicles, without additives,or with 10% benzyl alcohol, 20% benzyl benzoate, or a combination of 10%benzyl alcohol and 20% benzyl benzoate. See also FIG. 13C.

TABLE 2B Viscosity (Pa * s) of Various Oils with Additives 20% BenzylBenzoate with 10% Benzyl 20% Benzyl 10% Benzyl Solvent None AlcoholBenzoate alcohol Corn Oil 0.0550 0.0386 0.0371 0.0267 Sesame Oil 0.05940.0409 0.0395 0.0277 Peanut Oil 0.0671 0.0458 0.0434 0.0302 Cottonseed0.0591 0.0408 0.0396 0.0280 Oil Miglyol 0.0259 0.0193 0.0204 0.0154 812

Tables 2C and 2D show Glide Force (N) of various oil vehicles, withoutadditives, or with 10% benzyl alcohol, 20% benzyl benzoate, or acombination of 10% benzyl alcohol and 20% benzyl benzoate, using 23Gauge Needle or 27 Gauge Needle, respectively. See also FIGS. 13D and13E.

TABLE 2C Glide Force (N) of Various Oils with Additives, 23 Gauge Needle20% Benzyl Benzoate with 10% Benzyl 20% Benzyl 10% Benzyl Solvent NoneAlcohol Benzoate alcohol Corn Oil 13.4 8.7 8.0 7.5 Sesame Oil 12.4 9.78.7 6.1 Peanut Oil 14.6 12.9 10.9 6.6 Cottonseed 11.9 10.8 10.1 5.7 OilMiglyol 12.4 6.7 6.5 4.1 812

TABLE 2D Glide Force (N) of Various Oils with Additives, 27 Gauge Needle20% Benzyl Benzoate with 10% Benzyl 20% Benzyl 10% Benzyl Solvent NoneAlcohol Benzoate alcohol Corn Oil 91.5 66.4 53.0 48.5 Sesame Oil 92.668.0 63.2 46.1 Peanut Oil 85.6 74.0 58.2 49.2 Cottonseed 99.3 68.4 63.845.0 Oil Miglyol 46.8 35.4 37.7 27.2 812

Example 5 Blood Plasma Pharmacokinetics of Abiraterone in Rats and DogsFollowing Administration of Formulations of Abiraterone Prodrugs Example5A. PK Studies of Abiraterone and Abiraterone Acetate in Rats and Dogs

Several formulations were considered in the initial rat study. Theseformulations consisted of abiraterone acetate as a solution in castoroil or as a suspension in sodium phosphate buffer, 0.1% Tween andabiraterone suspension in castor oil or as an aqueous mixture of sodiumphosphate buffer, 0.1% Tween. The manufacturing of these long-acting IMformulations follows the general process of placing the drug in one vialand the solubilizing solution in a second vial and sterilizing each ofthe vials. Once the components are sterilized, they are mixed togetherunder sterile conditions to produce the final product. Sterilization isdone separately because the drug could possibly degrade during thesterilization process when the drug is in solution. Additionally, thissterilization process was selected over filtration sterilization due tothe viscosity of the oils or the suspension nature of two of theformulations.

An additional study was done using dogs as the animal model instead ofrats. Four formulations were taken into this study and they included asolution of abiraterone acetate in an aqueous system (given IV) andsolutions of abiraterone acetate in castor, 90% castor oil and 10%benzyl alcohol, or abiraterone acetate in 50% castor oil and 50% benzylbenzoate.

The above formulations were administered to either rats or dogs as an IVinjection or as IM injections to the hind leg(s) of each animal. Plasmasamples were pulled throughout the length of the study and analyzed forboth prodrug and abiraterone. The results of the rat study are providedin Table 3 and FIG. 1.

TABLE 3 Group Mean Plasma Pharmacokinetic Parameters for AbirateroneFollowing IM Injection of Various Formulations of Abiraterone orAbiraterone Acetate in Rats. T_(max) C_(max) AUC_(last) Group Animal(hr) (ng/mL) (ng * hr/mL) 1 N 5 5 5 Mean 39.2 21.6 934 SD 35.3 26.1 332CV % 90.2 121 35.5 2 N 5 5 5 Mean 8.00 3.84 329 SD 0.00 2.40 71.6 CV %0.00 62.6 21.8 3 N 5 5 4 Mean 2.60 13.3 163 SD 1.34 16.0 174 CV % 51.6120 107 4 N 3 3 0 Mean 1.67 1.43 SD 0.577 0.261 Group 1: abirateroneacetate solution in castor oil (70 mg/ml); Group 2: abiraterone acetatesuspension, sodium phosphate buffer, 0.1% Tween (70 mg/ml); Group 3:abiraterone suspension in castor oil (62.5 mg/ml); Group 4: abirateronesuspension, sodium phosphate buffer, 0.1% Tween (62.5 mg/ml)

The data from the rat study indicate that formulations containingabiraterone acetate preformed significantly better than the formulationscontaining abiraterone. Additionally, the formulation of Group 1, whichcontained abiraterone acetate in solution, performed better than theformulation of Group 2, which contained abiraterone acetate insuspension versus solution.

FIG. 1 depicts the mean plasma concentrations versus time profiles ofabiraterone in rats following IM injection of the abiraterone acetateformulation into the thigh muscle of five male rats at a dose of 35mg/kg. Blood samples for the evaluation of systemic exposure afterabiraterone acetate IM depot administration were collected at 1, 2, 4,8, 24, 48, 72 and 168 hours post-administration and analyzed forabiraterone as well as abiraterone acetate. In this study, theabiraterone acetate castor oil solution formulation was compared withabiraterone acetate aqueous suspension formulation and abirateroneaqueous and castor oil suspensions.

Initially, we attempted to administer abiraterone intramuscularly torats as a suspension consisting of vegetable oils and aqueous.Surprisingly, very low blood plasma levels were achieved withabiraterone itself (See FIG. 1). Also, surprisingly, the use ofabiraterone acetate in aqueous suspension resulted in low blood plasmalevels (See FIG. 1). Conversely, a vegetable oil solution of abirateroneacetate gave not only the highest blood plasma levels but also thelongest extended blood plasma concentrations of abiraterone in rats wheninjected intramuscularly (See FIG. 1).

The abiraterone acetate castor oil IM depot solution formulation showedsuperior plasma concentrations of abiraterone compared with theabiraterone and abiraterone acetate aqueous and castor oil suspensionsover the 168-hour period.

The results of the dog study are provided in Table 4 and FIG. 2.

TABLE 4 Group Mean Plasma Pharmacokinetic Parameters for AbirateroneFollowing IV and IM Injection of Abiraterone Acetate in Dogs. AUC_(last)AUC_(INF) Dose T_(max) C_(max) C_(max)/ (hr * ng/ AUC_(last)/ (hr * ng/AUC_(INF)/ t_(1/2) Group (mg/kg) Animal (hr) (ng/mL) Dose mL) Dose mLDose (hr) % F 1 10 N 9 9 9 9 9 9 9 9 Mean 0.0830 8560 856 5920 592 5990599 4.64 SD 0.00 2170 217 1590 159 1630 163 1.33 CV % 0.00 25.4 25.426.9 26.9 27.3 27.3 28.6 2 19 N 3 3 3 3 3 3 3 3 3 Mean 56.0 60.0 2.898910 469 8990 473 78.4 86.2 SD 13.9 14.4 0.684 1830 96.3 1790 94.2 10.29.58 CV % 24.7 23.7 23.7 20.5 20.5 19.9 19.92 13.1 11.1 3 27 N 3 3 3 3 33 3 3 3 Mean 56.0 97.7 3.26 14900 551 15000 555 87.3 85.7 SD 13.9 39.21.45 3940 146 3940 146 3.73 2.11 CV % 24.7 40.1 40.1 26.5 26.5 26.3 26.34.27 2.46 4 38 N 3 3 3 3 3 3 3 3 3 Mean 21.3 153 4.04 12400 327 12500329 66.0 61.7 SD 23.1 33.5 0.882 3350 88.2 3370 88.6 13.4 28.8 CV % 10821.8 21.8 26.9 26.9 27.0 27.0 20.2 46.7 Group 1: IV administration ofabiraterone acetate solution (33% aq HP-beta-cyclodextrin) dosed at 10mg/kg; Group 2: IM administration of abiraterone acetate solution incastor oil (66 mg/ml) dosed at 21 mg/kg; Group 3: IM administration ofabiraterone acetate solution in castor oil with 10% benzyl alcohol (91mg/ml) dosed at 30 mg/kg; Group 4: IM administration of abirateroneacetate solution in castor oil with 50% benzyl benzoate (124 mg/ml)dosed at 42 mg/kg.

The data from the dog study indicate that abiraterone acetate given as asolution in castor oil (with or without benzyl alcohol) producedmeasurable blood levels out to 504 hours. Additionally, although theformulation with benzyl benzoate produced measurable levels ofabiraterone acetate, the formulation was found to be irritating to thedogs at the injection site; one or two dogs were licking and biting atthe injection site and developed an open wound. This caused asignificant decrease in the fraction of prodrug absorbed from theseanimals and a significant decrease in the average fraction absorbed(61.7%) in this dose group. The absolute bioavailabilities for theseformulations were found to range between 61.7 and 86.2%.

FIG. 2 depicts the mean plasma concentrations versus time profiles ofabiraterone in dogs following IM injection of various abirateroneacetate formulations into the thigh muscle of male dogs (three dogs foreach formulation) at doses of 19, 27, and 38 mg/kg. Blood samples forthe evaluation of systemic exposure after abiraterone acetate IM depotadministration were collected at 0.5, 1, 2, 3, 4, 5, 8, 24, 48, 60, 120,168, 336, and 504 hours post-administration and analyzed for abirateroneas well as abiraterone acetate.

The abiraterone acetate IM depot solution formulations in castor oil,castor oil/benzyl alcohol, and castor oil/benzyl benzoate showedextended plasma concentrations of abiraterone over the 504-hour period.

An IV administration of abiraterone acetate was included in this study(dose of 10 mg/kg) to measure the bioavailability of the IM depotformulations. The bioavailabilities were determined to be 86.2%; 85.7%and 61.7%.

Computer-modeling was used to predict the human pharmacokinetic profileof abiraterone prodrugs administered IM to humans based on data obtainedfrom the IM rat and dog studies. The modeling predicted that an IM doseof 600 mg to 2,000 mg of abiraterone acetate administered to humansubjects every two to four weeks would produce the desired plasmapharmacokinetic profile in human subjects (that is, bioavailability ofgreater than 80%, C_(min) value of abiraterone greater than 1.0 ng/ml to8.4 ng/ml, e.g., greater than 1 ng/ml, greater than 2 ng/ml, greaterthan 4 ng/ml, or greater than 8.4 ng/ml, and C_(max) value ofabiraterone of approximately 10 ng/ml to 400 ng/ml for at least twoweeks). The predicted 600 mg IM dose of abiraterone acetate administeredevery two weeks should be compared to the current 1,000 mg/day oral doseof Zytiga® (which would be 14,000 mg for a two-week dosing period). Thehigher bioavailability of the IM delivery together with the eliminationof the food effect will lead to lower patient variability which togetherwith higher and less frequent plasma trough levels should lead to betterefficacy (ref C_(min)>8.4 ng/ml associated with improvedprostate-specific antigen response and improved progression-freesurvival in castration-resistant prostate cancer patients) (Carton etal., Eur. J. Can. 72:54, 2017).

Example 5B. PK Studies of Abiraterone Propionate and AbirateroneDecanoate in Dogs

This is a Single-Dose Bioavailability Study of Several AbirateronePro-drugs (Propionate and Decanoate) given as Intramuscular Injections(IM) and intravenous injections to Beagle Dogs.

The formulations and dosages used for this study are as follows:

-   -   1) Intramuscular (IM); Abiraterone propionate 197 mg/mL solution        in 10% Benzyl alcohol/90% Castor oil, dosed at 41 mg/kg;    -   2) Intramuscular (IM); Abiraterone propionate 168 mg/mL solution        in 10% Benzyl alcohol/90% Corn oil, dosed at 41 mg/kg;    -   3) Intramuscular (IM); Abiraterone decanoate 160 mg/mL solution        in 10% Benzyl alcohol/90% Castor oil; dosed at 50 mg/kg;    -   4) Intramuscular (IM); Abiraterone decanoate 170 mg/mL solution        in 10% Benzyl alcohol/90% Corn oil; dosed at 50 mg/kg;    -   5) Intravenous (IV); Abiraterone propionate 0.57 mg/mL solution        in 40% HP-b-CD/25 mM Na phosphate (pH 7.4) dosed at 1 mg/kg; and    -   6) Intravenous (IV); Abiraterone decanoate 0.37 mg/mL solution        in 40% HP-b-CD/25 mM Na phosphate (pH 7.4), dosed at 1.2 mg/kg.

Table 5 below summarizes the study design:

TABLE 5 Experimental Study Design Dose Dose Level Conc. # of Group TestArticle Route (mg/kg)* (mg/mL) Animals 1 Abiraterone Propionate IV 10.57 6 in 40% HP-beta- cyclodextrin 2 Abiraterone Decanoate IV 1.2 0.376 in 40% HP-beta- cyclodextrin 3 Abiraterone Propionate IM 41 197 3 in90% castor oil/10% benzyl alcohol 4 Abiraterone Propionate IM 41 168 3in 90% corn oil/10% benzyl alcohol 5 Abiraterone Decanoate IM 50 160 3in 90% castor oil/10% benzyl alcohol 6 Abiraterone Decanoate IM 50 170 3in 90% corn oil/10% benzyl alcohol *dose is Pro-drug concentration.Equivalent Abiraterone active dose was 0.82 mg/kg for IV administrationand 35 mg/kg for IM administration

All animals were dose via IV administration. Following a washout periodof 72 hours, all dogs were dosed via IM route. Doses were based on anassumed body weight of 10 kg. Following IV administration, blood wascollected at 0.083, 0.1667, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, and 24 hourspost dose administration. Following IM administration, blood wascollected at 0.5, 1, 2, 3, 4, 5, 8, and 12 hours and 1, 2, 3, 5, 7, 14,21, 28, 35, 42, 49, 56 (decanoate only) and 63 (decanoate only) dayspost dose administration (time of collection to approximate the time ofdose administration). Blood was processed to plasma and the resultingplasma samples were analyzed for the prodrug and abiraterone.

Following IV administration of abiraterone propionate, animals only had1 or 2 quantifiable plasma concentrations, as such, no reliablepharmacokinetic parameters could be assessed.

Pharmacokinetic analyses were performed on plasma concentration versustime data using Phoenix WinNonlin (v 8.1) non-compartmental analysisfunction (linear trapezoidal rule for AUC calculations). Nominal dosevalues and sampling times were used for calculations. For the purpose ofPK calculations, any concentration reported as “BLQ” was set equal tozero.

C_(max) and the corresponding T_(max) values were determined by directassessment of the concentration versus time data. All AUC calculationswere performed using the linear trapezoidal rule.

As data permitted, the terminal elimination rate constant (lambda z, λz)was calculated. The value of λz was determined by the slope of theregression line of the natural log transformed concentrations versustime with the following constraints:

Data points should be randomly distributed around a single straightline;

At least three data points post the C_(max) should be used in theregression;

The correlation coefficient (R²) of regression should be >0.80;

To optimize the reliability of the identified terminal phase (λz), wherepossible, the data points used to define the λz were manually selected.Lambda z profiles that did not meet the guidelines stated above excludedthe AUC_(INF), t_(1/2), CL/F, and Vz/F parameters for that animalprofile with an asterisk and excluded the results from summarydescriptive statistics.

The AUC_(INF) value was calculated as: AUC_(last)+(C_(last)/λz). CL/Fwas calculated as: Dose per dosing interval/(AUC_(INF)) and Vz/F wascalculated as: Dose per dosing interval/(AUC_(INF)*λz). Terminal t_(1/2)was calculated as: ln(2)/λz. If the lambda z interval was not at least2-fold greater than the calculated half-life, the half-life value wasflagged as unreliable with an asterisk and excluded from descriptivestatistics.

Mean plasma concentration versus time data are presented with standarddeviation (SD) and percent coefficient of variation (CV %) and reportedto three significant figures. PK parameter values are presented withmean, SD, and CV %. Individual T_(max) values were reported to twosignificant figures, while all other values and descriptive statisticsare reported to three significant figures.

Individual animal and group mean PK parameters for the pro-drugs andabiraterone, following IV administration, are presented in Table 6 andTable 7. Individual animal and group mean PK parameters for thepro-drugs and abiraterone, following IM administration, are presented inTable 8 and Table 9. Group mean plasma concentration versus timeprofiles, following administration to dogs, are plotted in FIG. 5through FIG. 10.

Results from IV Administration:

Following IV administration of abiraterone decanoate (pro-drug), a meanCL value of 8.88 mL/min/kg was calculated for the prodrug, which wasconsidered low clearance. Using a dose value of 0.84 mg/kg (assuming100% conversion of the prodrug to abiraterone) the mean CL/F value was97.8 mL/min/kg for abiraterone. The mean Vz value was 0.659 L/kg for thepro-drug and the mean Vz/F value 13.0 L/kg for abiraterone. The meant_(1/2) value for the prodrug and abiraterone was 0.86 hours and 1.5hours, respectively.

Exposure to abiraterone propionate was only observed in the first 2 timepoints after dose administration, as such no reliable PK parameterscould be calculated. Following IV administration of abirateronepropionate (pro-drug), the mean CL/F value for abiraterone was 114mL/min/kg, with a mean Vz/F value of 20.8 L/kg. The mean t_(1/2) valuefor abiraterone was 2.1 hours.

While the abiraterone C_(max) value was almost 4-fold higher followingIV administration of abiraterone propionate, the AUC values werecomparable (within 2-fold), suggesting marginal differences between thepro-drugs.

Results from IM Administration:

Following IM administration of the two decanoate formulations, meanabiraterone T_(max) value was 5.0 days for either of the twoformulations and the mean decanoate T_(max) values ranged between 0.11and 0.26 days between the formulations. The mean pro-drug andabiraterone exposures (as evidenced by C_(max) and AUC values) werewithin 2-fold between the 2 formulations. The terminal elimination phasefor the prodrug did not achieve a stable negative slope beyond the Day 7time points, as such no additional disposition parameters could beassessed. For abiraterone, the mean t_(1/2) value (terminal t_(1/2)) was23 and 24 days following administration in the 2 vehicles. Estimates ofthe absolute bioavailability for abiraterone are calculated using themean AUC_(INF) values following IV administration (145 h*ng/mL) and IMadministration (corrected for dose and time units=104 h*ng/mL for Group5 and 134 h*ng/mL for Group 6). The bioavailability was 72 and 92% forGroup 5 and 6, respectively.

Following IM administration of the two propionate formulations, meanabiraterone T_(max) values ranged between 0.56 or 0.61 days and the meanpropionate T_(max) values ranged between 0.11 and 0.26 days (2.3 and 6.2hours) between the formulations. The mean pro-drug and abirateroneexposures (as evidenced by C_(max) and AUC values) were within 2-foldbetween the 2 formulations. Excluding the Day 7 time point (no valuesbeyond Day 7), the mean t_(1/2) values for the pro-drug were between0.98 and 1.7 days following administration of the 2 different vehicles.For abiraterone, the mean t_(1/2) value was 1.8 and 4.5 days followingadministration in the 2 vehicles. Estimates of the absolutebioavailability for abiraterone are calculated using the mean AUC_(INF)values following IV administration (127 h*ng/mL) and IM administration(corrected for dose and time units=105 h*ng/mL for Group 3 and 94.1h*ng/mL for Group 4). The bioavailability was 83 and 74% for Group 3 and4, respectively.

Tables 6-9 and FIGS. 5-10 provide a summary of the PK studies of thisexample.

Computer-modeling was also used to predict the human pharmacokineticprofile of abiraterone decanoate administered IM to humans based on dataobtained from the rat and dog studies. Pharmacokinetic (PK) modellingand simulations were carried out using a fully-validated version (8.1)of WinNonlin Phoenix. Linear PK (exponential) models were fitted to theplasma concentration-time profiles of abiraterone following IVadministration of abiraterone (acetate or decanoate formulations) torats and dogs. The derived PK parameters of clearance (CL) anddistribution volume (Vss) were predicted in man by allometric scaling.The rate (K01) and extent (F) of bioavailability of abiraterone after IMadministration to dogs was estimated by deconvolution; values of K01 andF were assumed to be equivalent in man. The predicted PK parameters (CL,Vss, K01 and F) were used to simulate plasma concentration-time profilesin man after IM administration with various prescribed dose regimens(assuming linear kinetics of abiraterone.) The modeling predicted thatan IM dose of as low as 120 mg abiraterone decanoate every two weeks canachieve a therapeutically effective abiraterone plasma concentration inhuman with a C_(min) value of abiraterone at steady state greater thanabout 8 ng/ml, with a C_(max) value of abiraterone at steady state ofabout 14 ng/ml. The modeling also predicted that an IM dose ofabiraterone decanoate is suitable for once a month or once in more thana month dosing regimen in human, which can provide a therapeuticallyeffective abiraterone plasma concentration. For example, an IM dose ofabout 350 mg abiraterone decanoate once in 4 weeks is sufficient toprovide a C_(min) value of abiraterone at steady state greater thanabout 8 ng/ml. C_(max) value of abiraterone at steady state generally isdose proportional. See also FIG. 11A, FIG. 11B, FIG. 11C, and FIG. 11D.In light of this disclosure, in some cases, the dosing regimen can alsoinclude an initial dosing period with a higher dosing frequency or witha different abiraterone medication to achieve certain exposure ofabiraterone in a treated subject, which is then followed by a once amonth (or in more than a month) dosing regimen as described herein. Forexample, in some cases, the dosing regimen can include an initial IMdoses of abiraterone decanoate once in two weeks, e.g., for about 2-3doses, which is then followed by a once in a month administration ofabiraterone decanoate. Computer modeling predicted that such dosingregimen can achieve a C_(min) value of abiraterone at steady stategreater than about 8 ng/ml during the treatment period.

TABLE 6 Group Mean Abiraterone or Abiraterone Decanoate Plasma PKParameters Following IV Administration of 1.2 mg/kg AbirateroneDecanoate in Dogs (N = 6) Analyte Vz or CL or Dose T_(max) C_(max)AUC₀₋₈ AUC_(last) AUC_(INF) Vz/F CL/F t_(1/2) (mg/kg) (h) (ng/mL) (h *ng/mL) (h * ng/mL) (h * ng/mL) (L/kg) (mL/min/kg) (h) Abiraterone Mean0.833 57.2 135 143 145 13.0 97.8 1.54 0.83 SD 0.129 5.78 21.7 28.0 26.92.86 17.6 0.202 CV % 15.5 10.1 16.0 19.6 18.5 22.0 18.0 13.1 AbirateroneMean 0.0833 1890 2250 2260 2260 0.659 8.88 0.858 Decanoate SD 0.00 220143 141 142 0.0329 0.577 0.0202 1.2 CV % 0.00 11.6 6.35 6.26 6.27 5.006.50 2.36

TABLE 7 Group Mean Abiraterone or Abiraterone Propionate Plasma PKParameters Following IV Administration of 1 mg/kg Abiraterone Propionatein Dogs (N = 6) Analyte Vz or CL or Dose T_(max) C_(max) AUC₀₋₈AUC_(last) AUC_(INF) Vz/F CL/F t_(1/2) (mg/kg) (h) (ng/mL) (h * ng/mL)(h * ng/mL) (h * ng/mL) (L/kg) (mL/min/kg) (h) Abiraterone Mean 0.0833222 112 126 127 20.8 114 2.11 0.86 SD 0.00 30.8 11.9 14.1 14.2 2.53 12.90.142 CV % 0.00 13.9 10.7 11.2 11.2 12.2 11.3 6.76 Abiraterone Mean0.0833 27.1 Propionate SD 0.00 5.47 1.2 CV % 0.00 20.2

TABLE 8 Individual Animal and Group Mean Abiraterone or AbirateroneDecanoate Plasma PK Parameters Following IM Administration of 41 mg/kgAbiraterone Decanoate in Dogs T_(max) C_(max) AUC₀₋₂₈ AUC_(last)AUC_(INF) Vz/F CL/F t_(1/2) Analyte Group (d) (ng/mL) (d * ng/mL) (d *ng/mL) (d * ng/mL) (L/kg) (mL/min/kg) (d) Abiraterone 5 N 3 3 3 3 2 2 22 Mean 5.0 5.66 99.2 141 178 6560 138 23 SD 0.0 1.25 13.3 19.8 21.9 117017.0 1.3 CV % 0.00 22.1 13.4 14.1 12.3 17.8 12.3 5.53 Abiraterone 6 N 33 3 3 2 2 2 2 Mean 5.0 8.99 135 184 229 5330 107 24 SD 0.0 0.760 14.14.28 28.0 300 13.0 4.3 CV % 0.00 8.45 10.5 2.33 12.2 5.62 12.2 17.8Abiraterone 5 N 3 3 3 3 0 0 0 0 Decanoate Mean 0.26 4.15 16.6 30.0 SD0.21 0.673 1.72 8.07 CV % 81.2 16.2 10.3 26.9 Abiraterone 6 N 3 3 3 3 00 0 0 Decanoate Mean 0.11 6.61 21.9 35.9 SD 0.024 2.70 6.12 1.40 CV %21.8 40.9 27.9 3.89

TABLE 9 Individual Animal and Group Mean Abiraterone or AbirateronePropionate Plasma PK Parameters Following IM Administration of 50 mg/kgAbiraterone Propionate in Dogs (N = 3) T_(max) C_(max) AUC₀₋₂₈AUC_(last) AUC_(INF) Vz/F CL/F t_(1/2) Analyte Group (d) (ng/mL) (d *ng/mL) (d * ng/mL) (d * ng/mL) (L/kg) (mL/min/kg) (d) Abiraterone 3 Mean0.556 22.8 215 217 219 1050 112 4.53 SD 0.419 1.55 19.1 19.9 19.6 21910.5 0.949 CV % 75.5 6.79 8.88 9.20 8.92 20.9 9.38 21.0 Abiraterone 4Mean 0.611 74.9 198 190 196 467 124 1.81 SD 0.347 29.0 12.0 14.5 11.736.8 7.45 0.135 CV % 56.8 38.7 6.05 7.60 5.98 7.88 6.00 7.44 Abiraterone3 Mean 0.111 7.15 15.7 13.0 14.9 6870 1980 1.71 Propionate SD 0.04851.02 3.08 2.82 3.29 1570 481 0.502 CV % 43.7 14.3 19.6 21.7 22.1 22.924.3 29.3 Abiraterone 4 Mean 0.104 31.6 28.6 28.0 29.0 2110 1000 0.983Propionate SD 0.0953 18.4 5.67 5.97 5.29 937 181 0.264 CV % 91.6 58.319.8 21.3 18.2 44.4 18.0 26.9

Example 6A. Large Scale Preparation of Abiraterone Decanoate fromDecanoic Acid

To a suspension of Abiraterone (381.9 g, 1.09 mol) in dichloromethane(3500 mL) was added triethylamine (165 g, 1.64 mol) and a catalyticamount of DMAP (13.35 g, 0.109 mol). Decanoic acid (225 g, 1.31 mol) asa solution in dichloromethane (500 mL) was added to the suspension,followed by EDCI (293 g, 1.53 mol) and the reaction then agitated for 19h at 20-25° C.

10 wt % aq NaH₂PO₄ (4000 mL) was then added and the reaction wasagitated for 20 min. The organic layer was separated and extracted with10 wt % aq NaH₂PO₄ (2000 mL) and brine (2000 mL). The organic layer wassolvent exchanged with acetonitrile (4750 mL) and concentrated to 3100 gkeeping temperature of bath <40° C. The suspension was diluted withacetonitrile (900 g). The solids were isolated by filtration to afford510 g of crude abiraterone decanoate.

510 g of the crude abiraterone decanoate was dissolved in acetone (4000mL) at 40° C. The solution was filtered through a filter paper. Thefiltrate was transferred to a 12 L 3-neck flask, diluted to 5100 g andreheated to 40° C. to form a solution. The solution was cooled slowly to20° C. to form a suspension. This was diluted with water (1020 mL) andagitated at RT overnight. The solid was filtered and the flask wasrinsed with the filtrate and transferred to filter funnel. The wet cakewas transferred to drying tray and dried at 40-45° C. in vacuum ovenovernight to obtain 457.1 g (90% yield) as white solid. ¹H NMR (CDCl₃,400 MHz): d_(H) 8.62 (d, 1H, J=1.9 Hz), 8.31 (dd, 1H, J=4.9, 1.6 Hz),7.64 (dt, 1H, J=7.9, 1.9 Hz), 7.21 (ddd, 1H, J=8.0, 4.9, 0.8 Hz),6.01-5.97 (m, 1H), 5.44-5.40 (m, 1H), 4.68-4.58 (m, 1H), 2.39-2.23 (m,3H), 2.27 (t, 2H, J=7.6 Hz), 2.12-2.00 (m, 3H), 1.91-1.54 (m, 10H), 1.49(dt, 1H, J=11.9, 5.1 Hz), 1.35-1.23 (m, 12H), 1.20-1.07 (m, 2H), 1.08(s, 3H), 1.05 (s, 3H), 0.88 (t, 3H, J=6.8 Hz). Elemental Analysis,theoretical (corrected for 0.055% moisture level): C, 81.0%, H, 9.8%, N,2.8%; found: C, 81.1%, H, 10.2%, N, 2.8%.

The abiraterone decanoate obtained in this example was determined tohave a purity of 99.7% by weight using a HPLC method. For HPLC analysis,abiraterone decanoate samples were prepared in methanol at aconcentration of 0.05 mg/mL (for assay analysis) or 5 mg/mL (forimpurity analysis). The HPLC conditions are the following: HPLC column:Halo C8 (2.7 um, 100×3.0 mm); injection volume: 5 uL; ColumnTemperature: 40° C.; Sample Temperature: ambient; Detection: 210 nm;Mobile Phase: 25 mM Ammonium Acetate, pH 8.0 (MPA) and 95/5acetonitrile/tetrahydrofuran (MPB); Flow Rate: 0.6 ml/min; Gradient:starting with 65/35 MPA/MPB, in 35 minutes, reaching to 100% MPB, holdat 100% MPB until 40 minutes, at 40.10 minute, back to 65/35 MPA/MPB,and hold at 65/35 MPA/MPB until end at 45 minutes.

The white solid obtained in this example was also characterized by X-RayPowder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC).XRPD was conducted with Bruker's D8 Discover X-rat diffractometer, withTheta\theta vertical goniometer, using Vantec-500 as detector. Standardconditions: voltage 40 kV, current 40 mA, radiation, Cu, temperature,ambient, X-ray source exit slit size, 0.5 mm pinhole, snout collimator,0.5 mm, sample holder, ground quartz plate. Operating conditions:detector distance, 30 cm, Chi integration range, 4-40 degree 2θ, counttime, 120 seconds/frame, # of frames: 3, Theta 1 position, 4 degree,Theta 2 position, 4 degree, Frame width, 12, scan axis, coupled.Software used include GADDs software, General Area Detector DiffractionSystem, version 4.1.50; and DIFFRAC.EVA, version 4.0. DSC was performedwith TA Instruments Q2000 (Thermal Advantage V 5.0.0—qualified), with asample size of 2-10 mg, heating range from 25° C. to 250° C. at aheating rate of 10° C./min. Representative XRPD and DSC spectra areshown in FIGS. 12A-12B. A thermogravimetric analysis (TGA) was alsoperformed on this sample. TGA was performed with TA Instruments TGA Q500(Thermal Advantage V5.2.5—qualified), with a sample size of 5-20 mg,heating range from 25° C. to 150° C. at a heating rate of 10° C./min. Arepresentative TGA trace is shown in FIG. 12C.

Example 6B. Preparation of Abiraterone Decanoate Salts

Preparation of Abiraterone Decanoate Oxalate Salt

A solution of Abiraterone Decanoate (374 g, 744 mmoles) dissolved inisopropyl acetate to 5200 g and taken in a 12 L reactor. Oxalic acid(18.0 g) was charged and agitated for 2 h. The suspension was warmed to72° C. and agitated for 2 h. After cooling to 60° C., oxalic acid (20 g)and isopropyl acetate (1000 g) were charged. Heating was continued at60° C. for 30 min. More oxalic acid (20 g) and isopropyl acetate (600 g)were charged and heating was continued at 60° C. After 30 min moreoxalic acid (15.7 g) and isopropyl acetate (600 g) were charged.Reaction temperature was increased to 72° C. and heating was maintainedfor 18 h.

The reaction was then cooled to RT and further to 5-10° C. and theslurry was agitated for 2 h at the same temperature. The solids werefiltered and rinsed with cold isopropyl acetate (520 mL). The wet cakewas transferred to drying trays and dried in vacuum oven at 45-50° C.until constant weight of 410 g (92.8% yield). HPLC of the ABIRATERONEDECANOATE oxalate showed a purity of 99.62A %. ¹H NMR (CDCl₃, 400 MHz):d_(H) 12.62 (brs, 2H), 8.84 (d, 1H, J=1.8 Hz), 8.69 (d, 1H, J=5.5, 1.1Hz), 8.24 (dt, 1H, J=8.3, 1.7 Hz), 7.75 (dt, 1H, J=8.2, 5.5), 6.32-6.29(m, 1H), 5.44-5.39 (m, 1H), 4.68-4.58 (m, 1H), 2.42-2.31 (m, 3H), 2.28(t, 2H, J=7.5 Hz), 2.20-2.00 (m, 3H), 1.93-1.47 (m, 11H), 1.38-1.11 (m,14H), 1.10 (s, 6H), 0.88 (t, 3H, J=6.9 Hz).

Preparation of Abiraterone Decanoate HCl Salt

A solution of Abiraterone Decanoate (20 mmol) in EtOAc (140 mL) wastreated with 2 M HCl/ether (12 mL; 24 mmol; 1.2 eq.). The suspension washeated at 50° C. overnight; then cooled to 0-5° C. for 2 h. The solidsfiltered reasonably fast and it was rinsed with EtOAc to obtain 7.97 g(14.76 mmol; 74% yield) of ABIRATERONE DECANOATE HCl salt as whitesolid. ¹H NMR (CDCl₃, 400 MHz): d_(H) 8.70 (d, 1H, J=1.6 Hz), 8.58 (dd,1H, J=1.6, 5.6 Hz), 8.34 (dt, 1H, J=8.3, 1.6 Hz), 7.84 (dd, 1H, J=8.3,5.6 Hz), 6.37-6.33 (m, 1H), 5.44-5.39 (m, 1H), 4.68-4.58 (m, 1H),4.43-2.31 (m, 3H), 2.27 (t, 2H, J=7.5 Hz), 2.20-2.00 (m, 3H), 1.92-1.45(m, 13H), 1.36-1.23 (m, 13H), 1.21-1.10 (m, 2H), 1.09 (s, 3H), 1.08 (s,3H), 0.88 (t, 3H, J=6.9 Hz).

Preparation of Abiraterone Decanoate Benzene Sulfonic Salt

A solution of ABIRATERONE DECANOATE (0.57 mmnol) in ethyl acetate (10ml) was treated with benzene sulfonic acid (0.72 mmol. The resultingsolid ABIRATERONE DECANOATE benzene sulfonate salt (0.72 mmol) wasisolated by filtration (74% yield). ¹H NMR (CDCl₃, 400 MHz): d_(H) 8.87(d, 1H, J=1.7 Hz), 8.81 (brd, 1H, J=5.6 Hz), 8.32 (dt, 1H, J=8.1, 1.4Hz), 7.97-7.92 (m, 2H), 7.86 (dd, 1H, J=8.1, 5.6 Hz), 7.41-7.36 (m, 3H),6.36-6.32 (m, 1H), 5.44-5.38 (m, 1H), 4.68-4.56 (m, 1H), 2.59-2.30 (m,3H), 2.27 (t, 2H, J=7.5 Hz), 2.17-2.00 (m, 4H), 1.91-1.54 (m, 10H), 1.47(dt, 1H, J=12.1, 4.7 Hz), 1.35-1.22 (m, 15H), 1.20-1.10 (m, 1H), 1.08(s, 3H), 1.06 (s, 3H), 0.88 (t, 3H, J=7.2 Hz).

Preparation of Abiraterone Decanoate p-Toluene Sulfonate Salt

A solution of ABIRATERONE DECANOATE (0.57 mmnol) in ethyl acetate (10ml) was treated with p-Toluene sulfonic acid (0.72 mmol. The resultingsolid ABIRATERONE DECANOATE p-Toluene sulfonate salt was isolated byfiltration (64% yield). ¹H NMR (CDCl₃, 400 MHz): d_(H) 8.85 (d, 1H,J=1.7 Hz), 8.81 (brd, 1H, J=5.6 Hz), 8.31 (dt, 1H, J=8.4, 1.6 Hz), 7.85(dd, 1H, J=8.3, 5.8 Hz), 7.82 (dt, 1H, J=8.3, 1.6 Hz), 7.18 (d, 2H,J=8.0 Hz), 6.36-6.31 (m, 1H), 5.45-5.39 (m, 1H), 4.69-4.57 (m, 1H),2.57-2.30 (m, 6H), 2.28 (t, 2H, J=7.5 Hz), 2.19-2.00 (m, 4H), 1.93-1.54(m, 10H), 1.46 (dt, 1H, J=4.8, 1.20 Hz), 1.36-1.10 (m, 16H), 1.08 (s,3H), 1.06 (s, 3H), 0.88 (t, 3H, J=6.9 Hz).

Preparation of Abiraterone Decanoate Phosphate Salt

A solution of ABIRATERONE DECANOATE (1.0 mmmol) in isopropyl acetate (10ml) was treated with phosphoric acid (69.6 mg, 0.61 mmol). The resultingsolid ABIRATERONE DECANOATE phosphate salt was isolated by filtration(0.39 g, 65% yield). 1H NMR (CDCl₃, 400 MHz): d_(H) 9.75 (Brs, 4H), 8.60(Brs, 2H), 8.00 (Brd, 1H, J=7.7), 7.65 (Brs, 1H), 6.17 (Brs, 1H), 5.37(Brs, 1H), 4.59 (Brs, 1H), 2.45-2.16 (m, 6H), 2.09-1.78 (m, 5H),1.73-1.44 (m, 9H), 1.35-1.21 (m, 16H), 1.03 (s, 3H), 0.95 (s, 3H), 0.88(t, 3H, J=6.9 Hz).

Example 7. Studies of Abiraterone Decanoate in Rats and Monkeys andAllometric Scaling and Prediction of Plasma Profile in Human Example 7A.Studies of Abiraterone Decanoate in Monkeys

In the monkey PK studies, abiraterone decanoate formulation (90% CornOil, 10% Benzyl Alcohol, 192 mg/ml abiraterone decanoate) was dosedintramuscularly at 90 mg/kg in Male Cynomolgus Monkeys (n=3).

An IV dose of Abiraterone Decanoate (0.4 mg/ml solution in 40%HP-beta-cyclodextrin 25 mM Na phosphate buffer (pH 7.4) dosed at 1.2mg/kg (Average n=3) was used as comparison. For the IV dose, bloodsamples were taken at 0 hr, 0.083 hr, 0.17 hr, 0.25 hr, 0.5 hr, 0.75 hr,1 hr, 2 hr, 4 hr, 8 hr, and 24 hr. The results are shown in Table 10Aand FIG. 14A.

TABLE 10A Monkey IV PK parameters (arithmetic mean) C_(max) AUC_(inf)T_(max) (h) (ng/mL) (ng · h/mL) t_(1/2) (h) Abiraterone 0.083 2450 28602.27 Decanoate Abiraterone 0.83 123 376 2.59

Single Dose PK studies were carried out by injection of the abirateronedecanoate formulation (90% Corn Oil, 10% Benzyl Alcohol, 192 mg/mlabiraterone decanoate) intramuscularly at 90 mg/kg in Male CynomolgusMonkeys (n=3). The abiraterone decanoate formulation was injectedintramuscularly with split between 2 injections into the thigh on eachhind leg, using 27-Gauge needle. Blood samples were taken at 0 hr, 0.5hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr, 24 hr, 48 hr, 72 hr, 120 hr, 168hr, 336 hr, 504 hr, 672 hr, 840 hr, 1008 hr, 1176 hr, 1344 hr. Plasmaconcentration of Abiraterone Decanoate and Abiraterone were determined.The results are shown in Table 10B and FIG. 14B.

TABLE 10B Monkey single Dose PK parameters (geometric mean; Tmax is themedian) T_(max) C_(max) AUC t_(1/2) (days) (ng/mL) (ng · days/mL) (days)F (%) Abiraterone 0.74 11 69.6 10 0.8 Decanoate Abiraterone 6.3 10 15616 14

The progesterone, cortisol, and testosterone levels were also analyzedin this single dose PK study. As shown in FIG. 14C, following the singledose IM injection, a long duration of CYP17A1 inhibition was achieved asevidenced by the sustained increase of progesterone level and reductionof cortisol and testosterone level. The reduction in testosterone levelis modest as the monkeys in this study were non-castrated.

Multiple Dose PK studies were also carried out. In this study, multipledoses (each dose is 90 mg/kg) of the abiraterone decanoate formulation(90% Corn Oil, 10% Benzyl Alcohol, 192 mg/ml abiraterone decanoate) wereinjected intramuscularly in Male Cynomolgus Monkeys (n=3) at Day 0, Day7 and Day 35. Each dose of the abiraterone decanoate formulation wasinjected intramuscularly with split between 2 injections into the thighon each hind leg, using 27-Gauge needle. Blood samples were taken at 0hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr, 24 hr, 48 hr, 72 hr, 120hr, 168 hr, 192 hr, 216 hr, 240 hr, 288 hr, 336 hr, 504 hr, 672 hr, 840hr, 864 hr, 888 hr, 912 hr, 960 hr, 1008 hr, 1176 hr, 1344 hr, 1512 hr,1680 hr. Plasma concentration of Abiraterone Decanoate and Abirateronewere determined. The results were shown in FIG. 14E.

Example 7B. Studies of the Impact of Benzyl Benzoate on AbirateroneExposure in Monkeys

This example compares the pharmacokinetic behaviours of IM injections oftwo different abiraterone decanoate formulations:

-   -   Formulation 1, Abiraterone Decanoate in 90% Corn oil 10%, benzyl        alcohol, with the concentration of abiraterone decanoate of 207        mg/ml    -   Formulation 2—Abiraterone Decanoate in 70% Corn Oil, 10% benzyl        alcohol, 20% benzyl benzoate, with the concentration of        abiraterone decanoate of 209 mg/ml.

Formulations 1 and 2 were intramuscularly dosed into male cynomolgusmonkeys (n=1) at 100 mg/kg. The injections were given at day 0, day 7and day 14. Blood samples were taken at 0 hr, 1 hr, 2.5 hr, 5 hr, 7.5hr, 10 hr, 24 hr, 48 hr, 72 hr, 120 hr and 168 hr post each injection.Plasma abiraterone concentrations are shown in FIG. 14F.

As shown in FIG. 14F, IM injection of Formulation 2 unexpectedlyprovided significantly higher abiraterone plasma concentrations inmonkeys compared to IM injection of Formulation 1 at the same dose. Thistrend was also confirmed by parallel studies at different dosing levels.

Example 7C. Studies of Abiraterone Decanoate in Rats

In the rat PK studies, abiraterone decanoate formulation (90% Corn Oil,10% Benzyl Alcohol, 172 mg/ml abiraterone decanoate) was dosedintramuscularly at 90 mg/kg in male rats (n=5).

An IV dose of Abiraterone Decanoate (0.4 mg/ml solution in 40%HP-beta-cyclodextrin 25 mM Na phosphate buffer (pH 7.4) dosed at 1.2mg/kg (Average n=5) was used as comparison. For the IV dose, bloodsamples were taken at 0 hr, 0.083 hr, 0.17 hr, 0.25 hr, 0.5 hr, 0.75 hr,1 hr, 2 hr, 4 hr, 8 hr, and 24 hr. The results are shown in Table 11Aand FIG. 15A.

TABLE 11A Rat IV PK parameters T_(max) C_(max) AUC_(inf) (h) (ng/mL) (ng· h/mL) t_(1/2) (h) Abiraterone 0.083 1800 1020 3.2 DecanoateAbiraterone 0.167 55.1 75.6 1.5

Single Dose PK studies were carried out by injection of the abirateronedecanoate formulation (90% Corn Oil, 10% Benzyl Alcohol, 172 mg/mlabiraterone decanoate) intramuscularly at 90 mg/kg in Male rats (n=5).The abiraterone decanoate formulation was injected intramuscularly intothe thigh on hind leg, using 27-Gauge needle. Blood samples taken at 0hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr, 24 hr, 48 hr, 72 hr, 120hr, 168 hr, 336 hr, 504 hr, 672 hr, 840 hr, 1008 hr, 1176 hr, 1344 hr.Plasma concentration of Abiraterone Decanoate and Abiraterone weredetermined. The results are shown in Table 11B and FIG. 15B.

TABLE 11B Rat Single IM dose PK parameters T_(max) C_(max) AUC t_(1/2) F(days) (ng/mL) (ng · days/mL) (days) (%) Abiraterone 0.46 1.3 25 33 0.8Decanoate Abiraterone 11 1.19 53 23 22

Multiple Dose PK studies were also carried out. In this study, multipledoses (each dose is 90 mg/kg) of the abiraterone decanoate formulation(90% Corn Oil, 10% Benzyl Alcohol, 172 mg/ml abiraterone decanoate) wereinjected intramuscularly in Male rats (n=5) at Day 0, Day 7 and Day 35.Each dose of the abiraterone decanoate formulation was injectedintramuscularly into the thigh on hind leg, using 27-Gauge needle. Bloodsamples were taken at 0 hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 8 hr,24 hr, 48 hr, 72 hr, 120 hr, 168 hr, 192 hr, 216 hr, 240 hr, 288 hr, 336hr, 504 hr, 672 hr, 840 hr, 864 hr, 888 hr, 912 hr, 960 hr, 1008 hr,1176 hr, 1344 hr, 1512 hr, 1680 hr. Plasma concentration of AbirateroneDecanoate and Abiraterone were determined. The results are shown in FIG.15C.

Example 7D. Allometric Scaling and Prediction of Plasma Profile ofAbiraterone in Man

This pharmacokinetic (PK) analysis deals with the modelling of plasmaconcentrations of abiraterone following single intravenous (IV) andintramuscular (IM) administration of abiraterone to rats, dogs andmonkeys. PK parameters were derived from the PK model after IV dosingand IM dosing in rats, dogs and monkeys to predict, by means ofdeconvolution and allometric scaling, the plasma profile of abirateronein man after IM dosing of abiraterone decanoate.

Abiraterone decanoate was administered IV (1.2 mg/kg) and IM (90 mg/kg)to rats and monkeys; each animal received IV and IM doses. Abirateronedecanoate was administered IV (1.2 mg/kg) and IM (50 mg/kg) to dogs andIM (87 mg/kg) to dogs. Following single IV administration in rats, dogsand monkeys and single intramuscular administration in dogs, plasmasamples were taken up 24 h. Following single IM administration in rats,dogs and monkeys, plasma samples were taken up to 1344 h. The PK resultswere reported herein.

Pharmacokinetic Modelling:

Pharmacokinetic models (one and two-compartment with zero-order inputwere fitted (with or without weighting of 1/C predicted) to the plasmaconcentration profiles of abiraterone in individual animals, followingsingle intravenous administration of abiraterone to rats, dogs andmonkeys using WinNonlin Phoenix Version 8.2. The modelling was based onthe assumptions of linear (dose-proportional) and time-invariantkinetics and that there was complete conversion of the abirateronedecanoate pro-drug to abiraterone. The function (representingone-compartment disposition with zero-order absorption) was WinNonlinModel 2 and the function (representing two-compartment disposition withzero-order absorption) was WinNonlin Model 10. Weighting was included,dependent on the pattern of residuals (residual Y versus predictedconcentration or time) and precision of the estimated parameters. Theappropriate model was selected based on: (i) visual inspection of themodel fit to the data (ii) the lowest value of Akaike InformationCriterion (AIC) and (iii) precision of the estimated parameters (CV).Systemic clearance (CL) and apparent volume of distribution (V_(ss))were derived from the exponential functions.

Deconvolution:

The rate and extent of input from an intramuscular administration wassimulated by deconvolution using WinNonlin Phoenix Version 8.2.Deconvolution is based on linear systems analysis and is defined by theconvolution integral: G(t)=R(t)*H(t). G(t) is the measured plasmaconcentration profile after intramuscular dosing, H(t) is represented bythe exponential function described in Section 3.2 and R(t), the rate ofinput from the IM depot over time, is derived by deconvolution of theabove expression. The slope of the input rate versus time generates theinput rate constant (K₀₁). Integration of input rate versus timegenerates the cumulative input function and an estimate of absolutebioavailability.

Allometric Scaling to Man:

The plasma concentration profile in man after intramuscular dosing wassimulated based on the predictions of CL and Vss (to describe thedisposition of abiraterone), and rate and extent of input (absorption)into systemic circulation (bioavailability). The disposition ofabiraterone in animals was characterised by the PK parameters (CL andV_(ss)), derived from the exponential model. CL and V_(ss) in man werepredicted from CL and V_(ss) in animals by an allometric approach.V_(ss)=a·W^(x) where a is the intercept, W is bodyweight and x is theallometric exponent; then, log V_(ss)=x·log W+log a (derived from alog-log plot of body weight versus V_(ss) in the 3 species). CL in manwas derived by the data-driven method of Tang [⁵]; i.e. CLman/kg=0.407CL monkeys/kg. The rate and extent of input was derived bydeconvolution.

Results:

A bi-exponential function was considered to best represent the plasmaconcentration-time profiles of abiraterone following single intravenousadministration to rats, dogs and monkeys, respectively. Plasma clearance(CL) of abiraterone was 11414, 6469 and 2578 mL/h/kg in rats, dogs andmonkeys, respectively. Apparent of volume of distribution at steadystate (V_(ss)) of abiraterone was 22313, 14205 and 5732 mL/kg in rats,dogs and monkeys, respectively. See Table 12A below.

TABLE 12A Summary of PK parameters of abiraterone in rats, dogs andmonkeys following intravenous and intramuscular administration ofabiraterone decanoate CL Vss K01 F Species (mL/h/kg) (mL/kg) (/h) (%)Rats 11414 22313 0.00213 19 Dogs 6469 14205 0.00217 56 Monkeys 2578 57320.00213 14

Allometric scaling predicted CL (from monkeys only given the very highvalues of CL in rats and dogs) and V_(ss) (from rats, dogs and monkeys)in man of 73 L/h and 437 L, respectively. The predicted V_(ss) in manwas appreciably greater than total body water volume (42 L), indicatingextensive tissue distribution. The predicted CL in man was notappreciably different to hepatic blood flow (80 L/h).

Deconvolution of the IM profiles with the IV profiles providedestimations of the rate and extent of bioavailability of abiraterone. IMbioavailability in rats, dogs and monkeys was 19, 56 and 14%,respectively. The input (release from the IM depot) half-life after IMdosing in rats, dogs and monkeys was 325, 319 and 325 h, respectively.

Therefore, the parameters of CL (73 L/h), V_(ss) (437 L), K01 (0.00213h⁻¹) and F (56%) were used to simulate the plasma profile in man. SeeTable 12B, FIGS. 16A and 16B.

TABLE 12B Predicted parameters of abiraterone in man followingintramuscular administration of abiraterone decanoate* ParameterEstimate CL (L/h) 73 V_(ss) (L) 437 K01 (/h) 0.00213 t_(1/2) (h) 325 F(%) 56 *Predictions assume a one-compartment disposition withfirst-order absorption model and linear kinetics in man.

Following once monthly (i.e., every 4 weeks) intramuscular dose ofabiraterone at 1000 mg to man, the predicted C_(min) value was 5 ng/mLat steady state. See FIG. 16C. The inventors believe that humanbioavailability of the once monthly intramuscular administration at thisdosing level can be higher than the 56% used for the prediction in FIG.16C and approaching complete bioavailability. Assuming completebioavailability, the inventors believe that following once monthlyintramuscular dose of abiraterone at 1000 mg to man, the predictedC_(min) value would be 9.3 ng/mL at steady state. See FIG. 16D.

Conclusion:

Volume of distribution (V_(ss)) in man (437 L) was predicted byallometry with adequate correlation between rats, dogs and monkeys.V_(ss) indicates extensive tissue distribution in man. Systemicclearance (CL) in man (73 L/h) was predicted by allometry in monkeys. CLin man was not appreciably different to hepatic blood flow. Rate ofabsorption (absorption half-life of 325 h) and bioavailability (F of56%) was predicted from deconvolution of intramuscular and intravenousdata. Following once in four weeks intramuscular dose of abirateronedecanoate at 1000 mg to man, the predicted C_(min) was 5 ng/mL at steadystate.

Example 8. Studies of Abiraterone Isocaproate and Decanoate in Dogs

The objective of this study was to compare the pharmacokinetics (PK) oftwo different esters of abiraterone (isocaproate and decanoate) fromintramuscular (IM) formulations following single administration tobeagle dogs relative to a single intravenous (IV) formulation ofabiraterone isocaproate used to enable calculation of absolutebioavailability of the isocaproate ester.

Naïve male beagle dogs were obtained from Marshall Bioresources, NorthRose, N.Y. for use in this study. The animals were 6-7 months old andweighed 7.0-7.9 kilograms at the time of first dose administration.

Two groups of three male dogs/group underwent standard evaluations suchas body weight, clinical observations, and blood collection for PK. Onegroup of three dogs were dosed on Day 1 via IV with abirateroneisocaproate (Test article #1, abiraterone isocaproate in 40%HP-beta-cyclodextrin). Following a minimum washout of 72 hours, all sixdogs were dosed via IM. The three dogs that received the IV dose ofabiraterone isocaproate were given the abiraterone isocaproate IMpreparation (Test article #2, abiraterone isocaproate in 90% cornoil/10% benzyl alcohol) and the remaining three dogs were dosed withabiraterone decanoate IM preparation (Test article #3, abirateronedecanoate in 90% corn oil/10% benzyl alcohol). Doses were based on anassumed body weight of 10 kg, which could impact the calculated CL (orCL/F), Vz (or Vz/F) values, and the bioavailability assessment. Thestudy design is summarized in the following table:

Study Test Dose Dose Dose Conc* Dose Volume Number of Group ArticleRoute (mg/kg) (mg/mL) (mL/kg) Animals 1 #1 IV 1.0 0.3 3.3 3 2 #2 IM 77158 0.49 3 3 #3 IM 87 155 0.56 3 *Concentration of Prodrug.

Blood was collected predose and following IV administration, at 0.083,0.1667, 0.25, 0.5, 0.75, 1, 2, 4, and 24 hours post dose administration.Blood was collected just prior to dosing and following IMadministration, at 0.5, 1, 2, 3, 4, 5, 8, and 24 hours and 2, 3, 5, 7,14, 21, 28, 35, and 49 days post dose administration (time of collectionto approximate the time of dose administration). Blood was processed toplasma and the resulting plasma samples were analyzed for the prodrugand abiraterone.

Pharmacokinetic analyses were performed on plasma concentration versustime data using Phoenix WinNonlin (v 8.1) non-compartmental analysisfunction (linear trapezoidal rule for AUC calculations). See e.g.,Example 5B.

Results: Single-Dose Pharmacokinetics of Abiraterone and AbirateroneIsocaproate Following IV Administration of 1 mg/kg AbirateroneIsocaproate:

Evidence of systemic exposure to abiraterone and abiraterone isocaproatewas observed in all treated dogs following IV administration (Table 13Aand FIG. 17A). Following IV administration of abiraterone isocaproate(pro-drug), a mean CL value of 62.8 mL/min/kg was calculated for theprodrug, which was considered high clearance. Using a dose value of 0.78mg/kg (assuming 100% conversion of the prodrug to abiraterone) the meanCL/F value was 63.3 mL/min/kg for abiraterone. The mean Vz value was1.91 L/kg for the pro-drug and the mean Vz/F value 4.22 L/kg forabiraterone. The mean t/2 value for the prodrug and abiraterone was0.350 hours and 0.773 hours, respectively.

Single-Dose Pharmacokinetics of Abiraterone and Abiraterone IsocaproateFollowing IM Administration of Abiraterone Isocaproate:

Evidence of systemic exposure to abiraterone and abiraterone isocaproatewas observed in all treated dogs following IM administration (Table 13Band FIG. 17B), although it should be noted that there was highvariability in exposure parameters (C_(max) and AUC values) as CV %values ranged between 60 to 70%. Following IM administration, meanT_(max) values were 1.7 and 0.19 days for abiraterone and theisocaproate prodrug, respectively. The mean C_(max) values were 20.2 and106 ng/mL for abiraterone and the isocaproate prodrug, respectively. Themean AUC_(last) values were 266 and 281 day*ng/mL for abiraterone andthe isocaproate prodrug, respectively. The mean t_(1/2) values were 9.3and 7.4 days for abiraterone and the isocaproate prodrug, respectively.

Estimates of the absolute bioavailability for abiraterone werecalculated using the mean AUC_(INF) values following 0.78 mg/kg IVabiraterone isocaproate administration (206 h*ng/mL, or 131 h*ng/mL whencorrected for dose) and 60 mg/kg IM administration of abirateroneisocaproate (corrected for dose and time units=114 h*ng/mL). Theestimated abiraterone bioavailability from the isocaproate ester wascalculated at 87%, although these data should be interpreted withcaution since the dose was based on an assumed body weight of 10 kg.

Single-Dose Pharmacokinetics of Abiraterone and Abiraterone DecanoateFollowing IM Administration of Abiraterone Decanoate:

Evidence of systemic exposure to abiraterone and abiraterone decanoatewas observed in all treated dogs following IM administration (Table 13Band FIG. 17C). The variability in abiraterone exposure parameters(C_(max) and AUC values) was between 60 to 70%, while the decanoateexposure parameters had low variability with CV % values of <27%.Following IM administration, the mean T_(max) values were 5.7 and 0.71days for abiraterone and the decanoate prodrug, respectively. The meanC_(max) values were 7.82 and 45.0 ng/mL for abiraterone and thedecanoate prodrug, respectively. The mean AUC_(last) values were 176 and298 day*ng/mL for abiraterone and the decanoate prodrug, respectively.The mean t/2 values were 14 and 6.7 days for abiraterone and thedecanoate prodrug, respectively. Estimates of the absolutebioavailability for abiraterone are calculated using the mean AUC_(INF)values following 0.86 mg/kg IV administration of abiraterone decanoate(145 h*ng/mL, or 169 h*ng/mL when corrected for dose) and 60 mg/kg IMadministration (corrected for dose and time units=70.4 h*ng/mL). Theestimated abiraterone bioavailability was calculated at 42%, althoughthese data should be interpreted with caution since the dose was basedon an assumed body weight of 10 kg. The comparison of mean abirateroneplasma concentration profile following IM administration of abirateroneisocaproate or abiraterone decanoate is shown in FIG. 17D.

TABLE 13A Summary Abiraterone or Abiraterone Isocaproate Plasma PKParameters Following IV Administration in Dogs. Dose T_(max) C_(max)AUC₀₋₄ AUC_(last) AUC_(INF) Vz or Vz/F CL or CL/F t_(1/2) Analyte(mg/kg) (h) (ng/mL) (h * ng/mL) (h * ng/mL) (h * ng/mL) (L/kg)(mL/min/kg) (h) Abiraterone  0.78 N 3 3 3 3 3 3 3 3 Mean 0.17 165 159206 206 4.22 63.3 0.773 SD 0.0 17.2 3.48 12.5 12.5 0.125 3.85 0.0653 CV% 0.00 10.5 2.18 6.08 6.09 2.97 6.08 8.45 Isocaproate 1.0 N 3 3 3 3 3 33 3 Mean 0.083 751 269 269 269 1.91 62.8 0.350 SD 0.0 158 40.0 40.0 40.00.349 8.61 0.0228 CV % 0.00 21.0 14.9 14.9 14.9 18.3 13.7 6.52

TABLE 13B Summary Abiraterone or Abiraterone Prodrug Plasma PKParameters Following IM Administration in Dog T_(max) C_(max) AUC_(last)AUC_(INF) Vz/F CL/F t_(1/2) Group Analyte (d) (ng/mL) (d * ng/mL) (d *ng/mL) (L/kg) (mL/min/kg) (d) 2 Isocaproate N 3 3 3 3 3 3 3 Mean 0.19106 281 285 3640 238 7.40 SD 0.12 67.2 186 188 1950 114 1.36 CV % 61.963.5 66.1 65.9 53.6 47.8 18.4 2 Abiraterone N 3 3 3 3 3 3 3 Mean 1.720.2 266 275 3910 201 9.31 SD 1.2 13.2 192 197 2060 105 0.845 CV % 69.365.4 72.2 71.6 52.7 52.4 9.07 3 Decanoate N 3 3 3 3 3 3 3 Mean 0.71 45.0295 299 2850 207 6.68 SD 0.51 12.0 50.2 51.4 426 38.0 0.723 CV % 71.326.6 17.0 17.2 15.0 18.4 10.8 3 Abiraterone N 3 3 3 3 3 3 3 Mean 5.77.82 157 176 10900 386 13.8 SD 1.2 4.48 105 121 9600 350 0.466 CV % 20.457.3 67.1 68.8 88.1 90.5 3.37

Conclusion of Example 8:

Evidence of systemic exposure to abiraterone was observed in all treateddogs following dose administration. Comparison of the mean T_(max) andC_(max) values suggest that the isocaproate prodrug is more rapidlyabsorbed, with shorter T_(max) values and higher C_(max) values relativeto the decanoate prodrug. Mean abiraterone AUC values appeared to beless than 2-fold higher following IM administration of the isocaproatepro-drug when compared to the decanoate prodrug. The long half-lifevalues observed following IM administration relative to those valuesobserved following IV administration suggests that the prodrug has aslow release/absorption profile when administered via the IM route.There was some evidence that abiraterone half-life appeared to be longerfollowing the decanoate administration, which is likely due to theslower absorption of the decanoate prodrug.

Each reference referred to within this disclosure is hereby incorporatedin its respective entirety.

As used herein, the term “about” modifying an amount related to thedisclosure refers to variation in the numerical quantity that can occur,for example, through routine testing and handling; through inadvertenterror in such testing and handling; through differences in themanufacture, source, or purity of ingredients/materials employed in thedisclosure; and the like. As used herein, “about” a specific value alsoincludes the specific value, for example, about 10% includes 10%.Whether or not modified by the term “about”, the claims includeequivalents of the recited quantities. In one embodiment, the term“about” means within 20% of the reported numerical value.

With respect to aspects of the disclosure described as a genus, allindividual species are individually considered separate aspects of thedisclosure. If aspects of the disclosure are described as “comprising” afeature, embodiments also are contemplated “consisting of” or“consisting essentially of” the feature.

All of the various aspects, embodiments, and options described hereincan be combined in any and all variations.

Having now described a few embodiments of the invention, it should beapparent to those skilled in the art that the foregoing is merelyillustrative and not limiting, having been presented by way of exampleonly. Numerous modifications and other embodiments are within the scopeof one of ordinary skill in the art and are contemplated as fallingwithin the scope of the invention and any equivalent thereto. It can beappreciated that variations to the present invention would be readilyapparent to those skilled in the art, and the present invention isintended to include those alternatives. Further, because numerousmodifications will readily occur to those skilled in the art, it is notdesired to limit the invention to the exact construction and operationillustrated and described, and accordingly, all suitable modificationsand equivalents may be resorted to, falling within the scope of theinvention.

We claim:
 1. A compound of Formula I, or a pharmaceutically acceptablesalt thereof,

wherein R¹ is R¹⁰, O—R¹⁰, or NHR¹⁰, wherein R¹⁰ is selected from: aC₈₋₃₀ alkyl; a C₇₋₃₀ alkenyl; a C₇₋₃₀ alkynyl; an alkyl substituted witha cycloalkyl, which has a total number of carbons between 5 and 16; analkyl substituted with a phenyl, which has a total number of carbonsbetween 7 and 16; a cycloalkyl optionally substituted with one or morealkyl, which has a total number of carbons between 5 and 16; and


2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is a C₈₋₁₆ alkyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is an alkyl havingthe formula —(CH₂)_(n)—CH₃, wherein n is an integer selected from 7, 8,9, 10, 11, or
 12. 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is an alkyl having the formula—(CH₂)₈—CH₃ or


5. A pharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 6. A pharmaceutical composition comprisingabiraterone decanoate having the formula of:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 7. The pharmaceutical composition of claim 6,formulated for intramuscular injection, intradermal injection, orsubcutaneous injection.
 8. The pharmaceutical composition of claim 6,wherein the pharmaceutically acceptable carrier comprises apharmaceutically acceptable oil and optionally a furtherpharmaceutically acceptable solvent.
 9. The pharmaceutical compositionof claim 8, wherein the pharmaceutically acceptable oil comprises atriglyceride, and the further pharmaceutically acceptable solvent, ifpresent, comprises an alcohol, ester, and/or acid solvent.
 10. Thepharmaceutical composition of claim 9, wherein the pharmaceuticallyacceptable oil is selected from vegetable oil, castor oil, corn oil,sesame oil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil,and soybean oil, and the further pharmaceutically acceptable solvent, ifpresent, comprises benzyl alcohol, benzyl benzoate, or a combinationthereof.
 11. The pharmaceutical composition of claim 6, which comprisesthe abiraterone decanoate or pharmaceutically acceptable salt thereof inan amount sufficient to provide a therapeutically effective blood plasmaconcentration of abiraterone, or a blood plasma concentration ofabiraterone of about 1 ng/ml or higher, for a period of at least twoweeks, after a single administration to a subject having one or moredisorders selected from a sex hormone-dependent benign or malignantdisorder, a syndrome due to androgen excess, and a syndrome due toglucocorticoid excess.
 12. A method of treating one or more disordersselected from a sex hormone-dependent benign or malignant disorder, asyndrome due to androgen excess, and a syndrome due to glucocorticoidexcess, comprising administering to a subject in need thereof atherapeutically effective amount of the pharmaceutical composition ofclaim
 5. 13. The method of claim 12, wherein the administering is anintramuscular injection, intradermal injection, or subcutaneousinjection.
 14. The method of claim 12, wherein the pharmaceuticalcomposition is administered to the subject with or without food.
 15. Themethod of claim 12, wherein the one or more disorders are selected fromprostate cancer, breast cancer, ovarian cancer, bladder cancer,hepatocellular carcinoma, lung cancer, endometriosis, polycystic ovarysyndrome, Cushing's syndrome, Cushing's disease, classical ornonclassical congenital adrenal hyperplasia, precocious puberty,hirsutism, and combinations thereof.
 16. The method of claim 12, whereinthe one or more disorders is a sex hormone-dependent benign or malignantdisorder selected from castration resistant prostate cancer andcastration sensitive prostate cancer.
 17. The method of claim 12,wherein the one or more disorders is a sex hormone-dependent benign ormalignant disorder selected from metastatic castration resistantprostate cancer and metastatic castration sensitive prostate cancer. 18.The method of claim 12, wherein the subject is treated with agonadotropin-releasing hormone analog and/or bilateral orchiectomy. 19.The method of claim 12, further comprising administering to the subjecta corticosteroid.
 20. The method of claim 12, further comprisingadministering to the subject prednisone, prednisolone, and/ormethylprednisolone.
 21. The method of claim 12, wherein thepharmaceutical composition is administered to the subject once a week oronce in more than a week.
 22. The method of claim 12, wherein theadministering provides (a) a blood plasma concentration of abirateroneabove 1.0 ng/ml for a period of at least two weeks; (b) a single dose orsteady state C_(max) of abiraterone between about 10 ng/ml and about 400ng/ml; or (c) both (a) and (b).
 23. A pharmaceutical compositioncomprising a therapeutically effective amount of abiraterone decanoatehaving the formula of:

a pharmaceutically acceptable oil, and a pharmaceutically acceptablesolvent, wherein the abiraterone decanoate is in its basic form, whichis present at a concentration of about 25 mg/ml to about 500 mg/ml,wherein the pharmaceutical composition is formulated for intramuscularinjection, intradermal injection, or subcutaneous injection, wherein thepharmaceutical composition comprises the abiraterone decanoate in anamount of about 50 mg to about 2,000 mg.
 24. The pharmaceuticalcomposition of claim 23, wherein the pharmaceutically acceptable oilcomprises a triglyceride, and the pharmaceutically acceptable solventcomprises an alcohol, ester, and/or acid solvent.
 25. The pharmaceuticalcomposition of claim 24, wherein pharmaceutically acceptable oilcomprises a vegetable oil, castor oil, corn oil, sesame oil, cottonseedoil, peanut oil, poppy seed oil, tea seed oil, or soybean oil, thepharmaceutically acceptable solvent comprises benzyl alcohol and/orbenzyl benzoate, and wherein the abiraterone decanoate is present at aconcentration of about 50 mg/mL to about 300 mg/mL.
 26. A method oftreating prostate cancer, comprising administering to a subject in needthereof the pharmaceutical composition of claim 23 via intramuscularinjection, intradermal injection, or subcutaneous injection, once amonth or once in more than a month.
 27. The method of claim 26, whereinthe pharmaceutical composition is administered via intramuscularinjection.
 28. A method for preparing an abiraterone decanoateformulation suitable for parenteral administration to a subject having asex hormone-dependent benign or malignant disorder, a syndrome due toandrogen excess, and a syndrome due to glucocorticoid excess,comprising: a) mixing abiraterone decanoate, which has the formula of:

in a pharmaceutically acceptable carrier to form a mixture; andoptionally b) sterilizing the mixture formed in a).
 29. The method ofclaim 28, wherein the mixing comprises mixing a crystalline form ofabiraterone decanoate in the pharmaceutically acceptable carrier,wherein the crystalline form is characterized by an X-Ray PowerDiffraction spectrum having one or more of the following peaks: 4.6,6.9, 8.7, 17.5, 18.3, 18.6, 19.1, 19.6, and 20.8, degrees 2 theta,±0.2°; a Differential Scanning Calorimetry pattern having an endothermicpeak with an onset temperature at about 69.0° C.; or a combinationthereof.
 30. The method of claim 28, wherein the pharmaceuticallyacceptable carrier comprises a pharmaceutically acceptable oil and apharmaceutically acceptable solvent, wherein the pharmaceuticallyacceptable oil comprises a vegetable oil, castor oil, corn oil, sesameoil, cottonseed oil, peanut oil, poppy seed oil, tea seed oil, orsoybean oil, the pharmaceutically acceptable solvent comprises benzylalcohol or benzyl benzoate, and wherein the abiraterone decanoate ispresent at a concentration of about 50 mg/mL to about 300 mg/mL.